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The renin–angiotensin system (RAS) participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy.
Angiotensin II (AngII), the most vasoactive angiotensin peptide, participates in blood pressure regulation, aldosterone release, Na+ reabsorption from renal tubules, and electrolyte and fluid homeostasis. AngII is derived from angiotensinogen in two 2 proteolytic steps (Figure 26–1). First, renin, an enzyme released from the juxtaglomerular cells of the kidneys, cleaves the decapeptide angiotensin I (AngI) from the amino terminus of angiotensinogen (renin substrate). Then, angiotensin-converting enzyme (ACE) removes the carboxy-terminal dipeptide of AngI to produce the octapeptide AngII. AngII is an agonist ligand for 2 GPCRs, AT1 and AT2. The RAS includes local (tissue) RAS, alternative pathways for AngII synthesis (ACE-independent), formation of other biologically active angiotensin peptides (AngIII, AngIV, Ang[1–7]), and additional angiotensin-binding receptors (AT1, AT2, AT4, Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis.
Figure 26–1 Components of the RAS. The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways. ACE, angiotensin-converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulin-regulated aminopeptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT1, AT2, Mas, AT4, and PRR. *Exposure of the active site of renin can also occur nonproteolytically; see text and Figure 26–4.
RENIN AND THE PRORENIN/RENIN RECEPTOR. Renin is the major determinant of the rate of AngII production. It is synthesized, stored, and secreted by exocytosis into the renal arterial circulation by the granular juxtaglomerular cells (Figure 26–2) located in the walls of the afferent arterioles that enter the glomeruli. Renin is an aspartyl protease that cleaves the bond between residues 10 and 11 at the amino terminus of angiotensinogen to generate AngI. The active form of renin is a large glycoprotein that is synthesized as a preproenzyme and processed to prorenin. Prorenin may be activated in 2 ways: proteolytically, by proconvertase 1 or cathepsin B that remove 43 amino acids (propeptide) from prorenin's amino terminus to uncover the active site of renin (Figure 26–3); and nonproteolytically, when prorenin binds to the prorenin/renin receptor (PRR), resulting in conformational changes that unfold the propeptide and expose the active catalytic site of the enzyme. Both renin and prorenin are stored in the juxtaglomerular cells. The concentration of plasma prorenin is ~10x that of the active enzyme. The t1/2 of circulating renin is ~15 min.
Figure 26–2 Physiological pathways, feedback loops, and pharmacological regulation of the renin-angiotensin system. Schematic portrayal of the three major physiological pathways regulating renin release. See text for details. MD, macula densa; PGI2/PGE2 prostaglandins I2 and E2; NSAIDs, nonsteroidal anti-inflamatory drugs; Ang II, angiotensin II: ACE, angiotensin-converting enzyme. AT1 R, angiotensin subtype 1 receptor; NE/Epi, norepinephrine/epinephrine; JGCs, juxtaglomerular cells.
Figure 26–3 Regulation of J-G cell renin release by the macula densa. Mechanisms by which the macula densa regulates renin release. Changes in tubular delivery of NaCl to the macula densa cause appropriate signals to be conveyed to the juxtaglomerular cells. Sodium depletion upregulates nNOS and COX-2 in the macula densa to enhance production of prostaglandins (PGs). PGs and catecholamines stimulate cyclic AMP production and thence renin release from the juxtaglomerular cells. Increased NaCl transport depletes ATP and increases adenosine (ADO) levels. Adenosine diffuses to the juxtaglomerular cells and inhibits cyclic AMP production and renin release via Gi- coupled A1 receptors. Increased NaCl transport in the macula densa augments the efflux of ATP, which may inhibit renin release directly by binding to P2Y receptors and activating the Gq-PLC-IP3-Ca2+ pathway in juxtaglomerular cells. Circulating AngII also inhibits renin release on juxtaglomerular cells via Gq- coupled AT1 receptors.
CONTROL OF RENIN SECRETION. The secretion of renin from juxtaglomerular cells is controlled predominantly by 3 pathways (see Figure 26–2):
1. The macula densa pathway. The macula densa lies adjacent to the juxtaglomerular cells and is composed of specialized columnar epithelial cells in the wall of the cortical thick ascending limb that passes between the afferent and efferent arterioles of the glomerulus. A change in NaCl reabsorption by the macula densa results in the transmission to nearby juxtaglomerular cells of chemical signals that modify renin release. Increases in NaCl flux across the macula densa inhibit renin release, whereas decreases in NaCl flux stimulate renin release.
ATP, adenosine, and prostaglandins modulate the macula densa pathway (Figure 26–3). ATP and adenosine are released when NaCl transport increases: ATP acts on P2Y receptors and adenosine acts via the A1 adenosine receptor to inhibit renin release. Prostaglandins (PGE2, PGI2) are released when NaCl transport decreases, and stimulate renin release through enhancing cyclic AMP formation. Prostaglandin production is stimulated by inducible COX-2 and neuronal NO synthase.
Regulation of the macula densa pathway is more dependent on the luminal concentration of Cl– than Na+. NaCl transport into the macula densa is mediated by the Na+–K+–2CI– symporter (see Figure 26–3), and the half-maximal concentrations of Na+ and Cl– required for transport via this symporter are 2-3 and 40 mEq/L, respectively. Because the luminal concentration of Na+ at the macula densa usually is much greater than the level required for half-maximal transport, physiological variations in luminal Na+ concentrations at the macula densa have little effect on renin release (i.e., the symporter remains saturated with respect to Na+). Conversely, physiological changes in Cl– concentrations (20-60 mEq/L) at the macula densa profoundly affect macula densa–mediated renin release.
2. The intrarenal baroreceptor pathway. Increases and decreases in blood pressure or renal perfusion pressure in the preglomerular vessels inhibit and stimulate renin release, respectively. The immediate stimulus to secretion is believed to be reduced tension within the wall of the afferent arteriole. The release of renal prostaglandins may mediate in part the intrarenal baroreceptor pathway.
3. The β adrenergic receptor pathway is initiated by the release of NE from postganglionic sympathetic nerves. Activation of β1 receptors on juxtaglomerular cells (↑ cyclic AMP) enhances renin secretion.
Increased renin secretion enhances the formation of AngII, which stimulates AT1 receptors on juxtaglomerular cells to inhibit renin release, an effect termed short-loop negative feedback. The inhibition of renin release owing to AngII-induced increases in blood pressure has been termed long-loop negative feedback. AngII increases arterial blood via AT1 receptors; this effect inhibits renin release by: (1) activating high-pressure baroreceptors, thereby reducing renal sympathetic tone; (2) increasing pressure in the preglomerular vessels; and (3) reducing NaCl reabsorption in the proximal tubule (pressure natriuresis), which increases tubular delivery of NaCl to the macula densa.
Renin release is regulated by arterial blood pressure, dietary salt intake, and a number of pharmacological agents (see Figure 26–2). Loop diuretics stimulate renin release by decreasing arterial blood pressure and by blocking the reabsorption of NaCl at the macula densa. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and thereby decrease renin release. ACE inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors interrupt both the short- and long-loop negative feedback mechanisms and therefore increase renin release. Centrally acting sympatholytic drugs, as well as β adrenergic receptor antagonists, decrease renin secretion by reducing activation of β1 adrenergic receptors on juxtaglomerular cells.
ANGIOTENSINOGEN. AngI is cleaved by renin from the amino terminus of angiotensinogen, an abundant globular protein synthesized mainly by the liver. Angiotensinogen transcripts also are abundant in fat, certain regions of the CNS, and the kidneys. Angiotensinogen synthesis is stimulated by inflammation, insulin, estrogens, glucocorticoids, thyroid hormone, and AngII. During pregnancy, plasma levels of angiotensinogen increase several-fold owing to increased estrogen. Circulating levels of angiotensinogen are approximately equal to the Km of renin for its substrate (~1 μM). Consequently, the rate of AngII synthesis, and therefore blood pressure, can be influenced by changes in angiotensinogen levels. Oral contraceptives containing estrogen increase circulating levels of angiotensinogen and can induce hypertension.
ANGIOTENSIN-CONVERTING ENZYME (ACE, KININASE II, DIPEPTIDYL CARBOXYPEPTIDASE). ACE is an ectoenzyme and glycoprotein that contains 2 homologous domains, each with a catalytic site and a Zn2+-binding region. ACE is rather nonspecific and cleaves dipeptide units from substrates with diverse amino acid sequences. Preferred substrates have only 1 free carboxyl group in the carboxyl-terminal amino acid, and proline must not be the penultimate amino acid; thus, the enzyme does not degrade AngII. ACE is identical to kininase II, the enzyme that inactivates bradykinin and other potent vasodilator peptides. Although slow conversion of AngI to AngII occurs in plasma, the very rapid metabolism that occurs in vivo is due largely to the activity of membrane-bound ACE present on the luminal surface of endothelial cells throughout the vascular system.
The ACE gene contains an insertion/deletion polymorphism in intron 16 that explains 47% of the phenotypic variance in serum ACE levels. The deletion allele, associated with higher levels of serum ACE and increased metabolism of bradykinin, may confer an increased risk of hypertension, cardiac hypertrophy, atherosclerosis, and diabetic nephropathy.
ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2). Human ACE2 contains a single catalytic domain that is 42% identical to the 2 catalytic domains of ACE. ACE2 cleaves 1 amino acid from the carboxyl terminal to convert AngI to Ang(1-9) and AngII to Ang(1-7). AngII is the preferred substrate for ACE2 with 400-fold higher affinity than AngI. ACE2 may serve as a counterregulatory mechanism to oppose the effects of ACE. ACE2 regulates the levels of AngII and limits its effects by converting it to Ang(1-7), which binds to Mas receptors and elicits vasodilator and anti-proliferative responses. ACE2 is not inhibited by ACE inhibitors and has no effect on bradykinin. In animals, reduced expression of ACE2 is associated with hypertension, defects in cardiac contractility, and elevated levels of AngII.
ANGIOTENSIN PEPTIDES. AngI is rapidly converted to AngII. Angiotensin III (AngIII), also called Ang(2–8), can be formed either by the action of aminopeptidase on AngII or by the action of ACE on Ang(2-10). AngII and AngIII cause qualitatively similar effects. AngII and AngIII stimulate aldosterone secretion with equal potency; however, AngIII is only 25% and 10% as potent as AngII in elevating blood pressure and stimulating the adrenal medulla, respectively.
Ang(1-7) is formed by multiple pathways (see Figure 26–1). Ang(1-7) opposes many of the effects of AngII: It induces vasodilation, promotes NO production, potentiates the vasodilatory effects of bradykinin, and inhibits AngII-induced activation of ERK1/2; it has antiangiogenic, antiproliferative, and antithrombotic effects; and is cardioprotective in cardiac ischemia and heart failure. The effects of Ang(1-7) are mediated by a specific Mas receptor. ACE inhibitors increase tissue and plasma levels of Ang(1-7), both because AngI levels are increased and diverted away from AngII formation and because ACE contributes to the plasma clearance of Ang(1-7). AT1 receptor blockade boosts the levels of AngII that is converted to Ang(1-7) by ACE2.
Angiotensin IV (AngIV), also called Ang(3-8), is formed from AngIII through the action of aminopeptidase M and has potent effects on memory and cognition. Central and peripheral actions of AngIV are mediated through specific AT4 receptors identified as insulin-regulated aminopeptidases (IRAPs). AngIV binding to AT4 receptors inhibits the catalytic activity of IRAPs and enables accumulation of various neuropeptides linked to memory potentiation. Other actions include renal vasodilation, natriuresis, neuronal differentiation, hypertrophy, inflammation, and extracellular matrix remodeling. Analogs of angiotensin IV are being developed for their therapeutic potential in cognition in Alzheimer disease or head injury.
LOCAL (TISSUE) RENIN-ANGIOTENSIN SYSTEMS. Many tissues—including the brain, pituitary, blood vessels, heart, kidney, and adrenal gland—express mRNAs for renin, angiotensinogen, and/or ACE, and various cells cultured from these tissues produce renin, angiotensinogen, ACE, and angiotensins I, II, and III. Thus, it appears that local RASs exist independently of the renal/hepatic-based system and may influence vascular, cardiac, and renal function and structure. Activation of (tissue) RAS and local AngII production require the binding of renin or prorenin to the specific (pro)renin receptor (PRR), located on cell surfaces.
The (Pro)Renin Receptor. The PRR is the functional cell surface receptor that binds prorenin and renin with high affinity (KD ~6 and 20 nM, respectively) and specificity. Binding of (pro)renin to PRR enhances the catalytic activity of renin by 4- to 5-fold and induces non-proteolytic activation of prorenin (Figure 26–4). Bound, activated (pro)renin catalyzes the conversion of angiotensinogen to AngI, which can be converted to AngII by ACE located on the cell surface. AngII binds to AT1 receptors and activates intracellular signaling events that regulate cell growth, collagen deposition, fibrosis, inflammation, and apoptosis.
Figure 26–4 Biological activation of prorenin and pharmacological inhibition of renin. Prorenin is inactive; accessibility of angiotensinogen (AGT) to the catalytic site is blocked by the propeptide (black segment). The blocked catalytic site can be activated non-proteolytically by the binding of prorenin to the (pro)renin receptor (PRR) or by proteolytic removal of the propeptide. The competitive renin inhibitor, aliskiren, has a higher affinity (~0.1 μm) for the active site of renin than does AGT (~1 μm).
The binding of (pro)renin to PRR also induces AngII-independent signaling events that include activation of ERK1/2, p38, tyrosine kinases, TGF-β gene expression, and plasminogen activator inhibitor type 1 (PAI-1). These signaling pathways are not blocked by ACE inhibitors or AT1 receptor antagonists and are reported to contribute to fibrosis, nephrosis, and organ damage. PRR is abundant in the heart, brain, eye, adrenals, placenta, adipose tissue, liver, and kidneys.
Prorenin is no longer considered the inactive precursor of renin, as it is capable of activating local RAS and AngII-independent events that may contribute to organ damage. Circulating plasma concentrations of prorenin are 10-fold higher than renin in healthy subjects but are elevated to 100-fold in diabetic patients and are associated with increased risk of nephropathy, renal fibrosis, and retinopathy. The interaction of prorenin with PRR has become a target for therapeutic interventions.
Prorenin and renin also bind to the mannose-6-phosphate receptor (M6P), an insulin-like growth factor II receptor that functions as a clearance receptor. Knockout of the PRR gene is lethal. In humans, mutations in the PRR gene are associated with mental retardation and epilepsy, suggesting an important role in cognition, brain development, and survival.
ALTERNATIVE PATHWAYS FOR ANGIOTENSIN BIOSYNTHESIS. Angiotensinogen may be converted to AngI or directly to AngII by cathepsin G and tonin. Other enzymes that convert AngI to AngII include cathepsin G, chymostatin-sensitive AngII-generating enzyme, and heart chymase.
ANGIOTENSIN RECEPTORS. AngII and AngIII bind to specific GPCRs designated AT1 and AT2. Most of the known biological effects of AngII are mediated by the AT1 receptor. The AT1 receptor gene contains a polymorphism (A-to-C transversion in position 1166) associated with hypertension, hypertrophic cardiomyopathy, and coronary artery vasoconstriction. Preeclampsia is associated with the development of agonistic auto-antibodies against the AT1 receptor.
The functional role of the AT2 receptor is less defined, but may counterbalance many of the effects of the AT1 receptor by having antiproliferative, proapoptotic, vasodilatory, natriuretic, and antihypertensive effects. The AT2 receptor is distributed widely in fetal tissues, but its distribution is more restricted in adults. Expression of AT2 receptor is upregulated in cardiovascular diseases, including heart failure, cardiac fibrosis, and ischemic heart disease; however, the significance of increased AT2 receptor expression is unclear.
The Mas receptor mediates the effects of Ang(1-7), which include vasodilation and antiproliferation. Deletion of the Mas gene in transgenic mice reveals cardiac dysfunction.
The AT4 receptor mediates the effects of AngIV. This receptor is a single transmembrane protein (1025 amino acids) that co-localizes with the glucose transporter GLUT4. AT4 receptors are detectable in a number of tissues, such as heart, vasculature, adrenal cortex, and brain regions processing sensory and motor functions.
ANGIOTENSIN RECEPTOR-EFFECTOR COUPLING. AT1 receptors activate a large array of signal-transduction systems to produce effects that vary with cell type and that are a combination of primary and secondary responses. AT1 receptors couple to several heterotrimeric G proteins, including Gq, G12/13, and Gi. In most cell types, AT1 receptors couple to Gq to activate the PLCβ–IP3–Ca2+ pathway. Secondary to Gq activation, activation of PKC, PLA2, and PLD and eicosanoid production, as well as activation of Ca2+-dependent and MAP kinases and the Ca2+–calmodulin–dependent activation of NOS may occur. Activation of Gi may occur and will reduce the activity of adenylyl cyclase, lowering cellular cyclic AMP content. The βγ subunits of Gi and activation of G12/13 lead to activation of tyrosine kinases and small G proteins such as Rho. Ultimately, the JAK/STAT pathway may be activated and a variety of transcriptional regulatory factors induced. AT1 receptors also stimulate the activity of a membrane-bound NADH/NADPH oxidase that generates reactive oxygen species (ROS). ROS may contribute to biochemical effects (activation of MAP kinase, tyrosine kinase, and phosphatases; inactivation of NO; and expression of monocyte chemoattractant protein-1) and physiological effects (acute effects on renal function, chronic effects on blood pressure, and vascular hypertrophy and inflammation). The presence of other receptors may alter the response to AT1 receptor activation. For example, AT1 receptors heterodimerize with bradykinin B2 receptors, a process that enhances AngII sensitivity in preeclampsia.
Signaling from AT2 receptors is mediated by G protein-dependent and independent pathways. Stimulation of AT2 receptor activates phosphoprotein phosphatases, K+ channels, synthesis of NO and cyclic GMP, bradykinin production, and inhibition of Ca2+ channel functions. AT2 receptors may possess constitutive activity: overexpression of AT2 receptors can induce NO production in vascular smooth muscle cells and hypertrophy in cardiac myocytes through an intrinsic activity of the AT2 receptor independent of AngII binding.
AngII increases total peripheral resistance (TPR) and alters renal function and cardiovascular structure through direct and indirect mechanisms (Figure 26–5).
Figure 26–5 Major effects of AngII. NE, norepinephrine.
Direct Vasoconstriction. AngII constricts precapillary arterioles and, to a lesser extent, postcapillary venules by activating AT1 receptors located on vascular smooth muscle cells and stimulating the Gq–PLC–IP3–Ca2+ pathway. AngII has differential effects on vascular beds. Direct vasoconstriction is strongest in the kidneys (see Figure 26–5) and the splanchnic vascular bed. AngII-induced vasoconstriction is much less in vessels of the brain, lungs, and skeletal muscle. Nevertheless, high circulating concentrations of AngII may decrease cerebral and coronary blood flow.
Enhancement of Peripheral Noradrenergic Neurotransmission. AngII augments NE release from sympathetic nerve terminals by inhibiting the reuptake of NE into nerve terminals and by enhancing the vascular response to NE.
Effects on the CNS. AngII increases sympathetic tone. Small amounts of AngII infused into the vertebral arteries cause an increase in arterial blood pressure. This response reflects effects of the hormone on circumventricular nuclei that are not protected by a blood-brain barrier. Circulating AngII also attenuates baroreceptor-mediated reductions in sympathetic discharge, thereby increasing arterial pressure. The CNS is affected both by blood-borne AngII and by AngII formed within the brain. The brain contains all components of the RAS. AngII also causes a centrally mediated dipsogenic (thirst) effect and enhances the release of vasopressin from the neurohypophysis.
Release of Catecholamines from the Adrenal Medulla. AngII stimulates the release of catecholamines from the adrenal medulla by depolarizing chromaffin cells.
Alteration of Renal Function. AngII has pronounced effects on renal function, reducing the urinary excretion of Na+ and water while increasing the excretion of K+. The overall effect of AngII on the kidneys is to shift the renal pressure–natriuresis curve to the right (Figure 26–6).
Figure 26–6 Pressure-natriuresis curve: effects of Na+ intake on renin release (AngII formation) and arterial blood pressure. Inhibition of the renin-angiotensin system will cause a large drop in blood pressure in Na+-depleted individuals. (Modified with permission from Jackson EK, Branch RA, et al: Physiological functions of the renal prostaglandin, renin, and kallikrein systems, in Seldin DW, Giebisch GH, eds: The Kidney: Physiology and Pathophysiology, Vol 1. Philadelphia: Lippincott Williams & Wilkins, 1985, p 624.)
Direct Effects of Angiotensin II on Na+ Reabsorption in the Renal Tubules. Very low concentrations of AngII stimulate Na+/H+ exchange in the proximal tubule—an effect that increases Na+, Cl–, and bicarbonate reabsorption. Approximately 20-30% of the bicarbonate handled by the nephron may be affected by this mechanism. AngII also increases the expression of the Na+–glucose symporter in the proximal tubule. Paradoxically, at high concentrations, AngII may inhibit Na+ transport in the proximal tubule. AngII also directly stimulates the Na+–K+–2Cl– symporter in the thick ascending limb.
Release of Aldosterone from the Adrenal Cortex. AngII stimulates the zona glomerulosa of the adrenal cortex to increase the synthesis and secretion of aldosterone, and augments responses to other stimuli (e.g., adrenocorticotropic hormone, K+). Increased output of aldosterone is elicited by concentrations of AngII that have little or no acute effect on blood pressure. Aldosterone acts on the distal and collecting tubules to cause retention of Na+ and excretion of K+ and H+. The stimulant effect of AngII on aldosterone synthesis and release is enhanced under conditions of hyponatremia or hyperkalemia and is reduced when concentrations of Na+ and K+ in plasma are altered in the opposite directions.
Altered Renal Hemodynamics. AngII reduces renal blood flow and renal excretory function by directly constricting the renal vascular smooth muscle, by enhancing renal sympathetic tone (a CNS effect), and by facilitating renal adrenergic transmission (an intrarenal effect). AngII-induced vasoconstriction of preglomerular microvessels is enhanced by endogenous adenosine owing to signal-transduction systems activated by AT1 and the adenosine A1 receptor. AngII influences glomerular filtration rate (GFR) by means of several mechanisms:
• Constriction of the afferent arterioles, which reduces intraglomerular pressure and tends to reduce GFR
• Contraction of mesangial cells, which decreases the capillary surface area within the glomerulus available for filtration and also tends to decrease GFR
• Constriction of efferent arterioles, which increases intraglomerular pressure and tends to increase GFR
Normally, GFR is slightly reduced by AngII; however, during renal artery hypotension, the effects of AngII on the efferent arteriole predominate so that AngII increases GFR. Thus, blockade of the RAS may cause acute renal failure in patients with bilateral renal artery stenosis or in patients with unilateral stenosis who have only a single kidney.
EFFECTS ON CARDIOVASCULAR STRUCTURE. Pathological alterations involving cardiac hypertrophy and remodeling increase morbidity and mortality. The cells involved include vascular smooth muscle cells, cardiac myocytes, and fibroblasts. AngII stimulates the migration, proliferation, and hypertrophy of vascular smooth muscle cells; causes hypertrophy of cardiac myocytes; and increases extracellular matrix production by cardiac fibroblasts. AngII alters extracellular matrix formation and degradation indirectly by increasing aldosterone. In addition to the direct cellular effects of AngII on cardiovascular structure, changes in cardiac preload (volume expansion owing to Na+ retention) and afterload (increased arterial blood pressure) probably contribute to cardiac hypertrophy and remodeling. Arterial hypertension also contributes to hypertrophy and remodeling of blood vessels.
ROLE OF THE RAS IN LONG-TERM MAINTENANCE OF ARTERIAL BLOOD PRESSURE DESPITE EXTREMES IN DIETARY NA+ INTAKE. Arterial blood pressure is a major determinant of Na+ excretion. This is illustrated graphically by plotting urinary Na+ excretion versus mean arterial blood pressure (see Figure 26–6), a plot known as the renal pressure–natriuresis curve. Over the long term, Na+ excretion must equal Na+ intake. The RAS plays a major role in maintaining a constant set point for long-term levels of arterial blood pressure despite extreme changes in dietary Na+ intake. When dietary Na+ intake is low, renin release is stimulated, and AngII acts on the kidneys to shift the renal pressure–natriuresis curve to the right. Conversely, when dietary Na+ is high, renin release is inhibited, and the withdrawal of AngII shifts the renal pressure–natriuresis curve to the left. When modulation of RAS is blocked by drugs, changes in salt intake markedly affect long-term levels of arterial blood pressure.
Clinical interest focuses on developing inhibitors of the RAS. Three types of inhibitors are used therapeutically (Figure 26–7):
Figure 26–7 Inhibitors of the RAS. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor.
• ACE inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs)
• Direct renin inhibitors (DRIs)
While all of these classes of agents will reduce the actions of AngII and lower blood pressure, they have different effects on the individual components of the RAS (Table 26–1).
Table 26–1
Effects of Antihypertensive Agents on Components of the RAS
PHARMACOLOGICAL EFFECTS. The effect of ACE inhibitors on the RAS is to inhibit the conversion of AngI to the active AngII. Inhibition of AngII production will lower blood pressure and enhance natriuresis. ACE is an enzyme with many substrates; thus, there are other consequences of its inhibition, including inhibition of bradykinin degradation. ACE inhibitors increase by 5-fold the circulating levels of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline, which may contribute to the cardioprotective effects of ACE inhibitors. In addition, ACE inhibitors will increase renin release and the rate of formation of AngI by interfering with both short- and long-loop negative feedbacks on renin release (see Figure 26–2). Accumulating AngI is directed down alternative metabolic routes that increase production of vasodilator peptides such as Ang(1-7).
Clinical Pharmacology. ACE inhibitors can be classified into 3 broad groups based on chemical structure: (1) sulfhydryl-containing ACE inhibitors structurally related to captopril; (2) dicarboxyl-containing ACE inhibitors structurally related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, perindopril); and (3) phosphorus-containing ACE inhibitors structurally related to fosinopril. Many ACE inhibitors are ester-containing prodrugs that are 100-1000 times less potent but have a better oral bioavailability than the active molecules. With the exceptions of fosinopril and spirapril (which display balanced elimination by the liver and kidneys), ACE inhibitors are cleared predominantly by the kidneys. Impaired renal function significantly diminishes the plasma clearance of most ACE inhibitors, and dosages of these drugs should be reduced in patients with renal impairment.
All ACE inhibitors block the conversion of AngI to AngII and have similar therapeutic indications, adverse-effect profiles, and contraindications. Because hypertension usually requires lifelong treatment, quality-of-life issues are an important consideration in comparing antihypertensive drugs. ACE inhibitors differ markedly in tissue distribution, and it is possible that this difference could be exploited to inhibit some local (tissue) RAS while leaving others relatively intact.
Captopril (CAPOTEN, others). Captopril is a potent ACE inhibitor with a Ki of 1.7 nM. Given orally, captopril is absorbed rapidly and has a bioavailability ~75%. Bioavailability is reduced by 25-30% with food. Peak concentrations in plasma occur within an hour, and the drug is cleared rapidly with a t1/2 ~2 h. Most of the drug is eliminated in urine, 40-50% as captopril and the rest as captopril disulfide dimers and captopril–cysteine disulfide. The oral dose of captopril ranges from 6.25-150 mg 2-3 times daily, with 6.25 mg 3 times daily or 25 mg twice daily being appropriate for the initiation of therapy for heart failure or hypertension, respectively.
Enalapril (VASOTEC, others). Enalapril maleate is a prodrug that is hydrolyzed by esterases in the liver to enalaprilat. Enalaprilat is a potent inhibitor of ACE with a Ki of 0.2 nM. Enalapril is absorbed rapidly and has an oral bioavailability of ~60% (not reduced by food). Although peak concentrations of enalapril in plasma occur within an hour, enalaprilat concentrations peak only after 3-4 h. Enalapril has a t1/2 ~1.3 h, but enalaprilat, because of tight binding to ACE, has a plasma t1/2 of ~11 h. Elimination is by the kidneys as either intact enalapril or enalaprilat. The oral dosage of enalapril ranges from 2.5-40 mg daily, with 2.5 and 5 mg daily being appropriate for the initiation of therapy for heart failure and hypertension, respectively.
Enalaprilat (VASOTEC INJECTION, others). Enalaprilat is not absorbed orally but is available for intravenous administration when oral therapy is not appropriate. For hypertensive patients, the dosage is 0.625 to 1.25 mg given intravenously over 5 min. This dosage may be repeated every 6 h.
Lisinopril (PRINIVIL, ZESTRIL, others). Lisinopril is the lysine analog of enalaprilat; unlike enalapril, lisinopril itself is active. Lisinopril is absorbed slowly, and incompletely (~30%) after oral administration (not reduced by food); peak concentrations in plasma are achieved in ~7 h. It is cleared as the intact compound by the kidney, and its t1/2 in plasma is ~12 h. Lisinopril does not accumulate in tissues. The oral dosage of lisinopril ranges from 5–40 mg daily (single or divided dose), with 5 and 10 mg daily being appropriate for the initiation of therapy for heart failure and hypertension, respectively. A daily dose of 2.5 mg and close medical supervision is recommended for patients with heart failure who are hyponatremic or have renal impairment.
Benazepril (LOTENSIN, others). Hepatic esterases transforms benazepril, a prodrug, into benazeprilat. Benazepril is absorbed rapidly but incompletely (37%) after oral administration (only slightly reduced by food). Benazepril is metabolized to benazeprilat and to the glucuronide conjugates of benazepril and benazeprilat, which are excreted into both the urine and bile; peak concentrations of benazepril and benazeprilat in plasma are achieved in 0.5-1 h and 1-2 h, respectively. Benazeprilat has a plasma t1/2 of 10-11 h. With the exception of the lungs, benazeprilat does not accumulate in tissues. The oral dosage of benazepril ranges from 5-80 mg daily (single or divided dose).
Fosinopril (MONOPRIL, others). Cleavage of the ester moiety by hepatic esterases transforms fosinopril into fosinoprilat. Fosinopril is absorbed slowly and incompletely (36%) after oral administration (rate but not extent reduced by food). Fosinopril is largely metabolized to fosinoprilat (75%) and to the glucuronide conjugate of fosinoprilat. These are excreted in both the urine and bile; peak concentrations of fosinoprilat in plasma are achieved in ~3 h. Fosinoprilat has an effective plasma t1/2 of ~11.5 h; its clearance is not significantly altered by renal impairment. The oral dosage of fosinopril ranges from 10-80 mg daily (single or divided dose). The initial dose is reduced to 5 mg daily in patients with Na+ or water depletion or renal failure.
Trandolapril (MAVIK, others). An oral dose of trandolapril is absorbed without reduction by food and produces plasma levels of trandolapril (10% bioavailability) and trandolaprilat (70% bioavailability). Trandolaprilat is ~8 times more potent than trandolapril as an ACE inhibitor. Trandolapril is metabolized to trandolaprilat and to inactive metabolites that are recovered in the urine (33%, mostly trandolaprilat) and feces (66%). Trandolaprilat displays biphasic elimination kinetics with an initial t1/2 of ~10 h (the major component of elimination), followed by a more prolonged t1/2 (owing to slow dissociation of trandolaprilat from tissue ACE). Plasma clearance of trandolaprilat is reduced by both renal and hepatic insufficiency. The oral dosage ranges from 1 to 8 mg daily (single or divided dose). The initial dose is 0.5 mg in patients who are taking a diuretic or who have renal impairment, and 2 mg for African Americans.
Quinapril (ACCUPRIL, others). Cleavage of the ester moiety by hepatic esterases transforms quinapril, a prodrug, into quinaprilat. Quinapril is absorbed rapidly (peak concentrations are achieved in 1 h), and the rate, but not extent, of oral absorption (60%) may be reduced by food (delayed peak). Quinaprilat and other minor metabolites of quinapril are excreted in the urine (61%) and feces (37%). Conversion of quinapril to quinaprilat is reduced in patients with diminished liver function. The initial t1/2 of quinaprilat is ~2 h; a prolonged terminal t1/2 ≈25 h may be due to high-affinity binding of the drug to tissue ACE. The oral dosage range of quinapril is 5-80 mg daily.
Ramipril (ALTACE, others). Cleavage of the ester moiety by hepatic esterases transforms ramipril into ramiprilat, an ACE inhibitor that in vitro is about as potent as benazeprilat and quinaprilat. Ramipril is absorbed rapidly (peak concentrations are achieved in 1 h), and the rate but not extent of its oral absorption (50-60%) is reduced by food. Ramipril is metabolized to ramiprilat and to inactive metabolites that are excreted predominantly by the kidneys. Ramiprilat displays triphasic elimination kinetics with half-lives of 2-4 h, 9-18 h, and >50 h. This triphasic elimination is due to extensive distribution to all tissues (initial t1/2), clearance of free ramiprilat from plasma (intermediate t1/2), and dissociation of ramiprilat from tissue ACE (long terminal t1/2). The oral dosage range of ramipril is 1.25-20 mg daily (single or divided dose).
Moexipril (UNIVASC, others). Moexipril's antihypertensive activity is due to its de-esterified metabolite, moexiprilat. Moexipril is absorbed incompletely, with bioavailability as moexiprilat of ~13%. Bioavailability is markedly decreased by food. The elimination t1/2 varies between 2 and 12 h. The recommended dosage range is 7.5-30 mg daily (single or divided doses). The dosage range is halved in patients who are taking diuretics or who have renal impairment.
Perindopril (ACEON). Perindopril erbumine is a prodrug, and 30-50% of systemically available perindopril is transformed to perindoprilat by hepatic esterases. Although the oral bioavailability of perindopril (75%) is not affected by food, the bioavailability of perindoprilat is reduced by ~35%. Perindopril is metabolized to perindoprilat and to inactive metabolites that are excreted predominantly by the kidneys. Perindoprilat displays biphasic elimination kinetics with half-lives of 3-10 h (the major component of elimination) and 30-120 h (owing to slow dissociation of perindoprilat from tissue ACE). The oral dosage range is 2-16 mg daily (single or divided dose).
THERAPEUTIC USES OF ACE INHIBITORS. Drugs that interfere with RAS play a prominent role in the treatment of cardiovascular disease, the major cause of mortality in modern Western societies.
ACE Inhibitors in Hypertension. Inhibition of ACE lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various hypertensive states except when high blood pressure is due to primary aldosteronism (see Chapter 27). The initial change in blood pressure tends to be positively correlated with plasma renin activity (PRA) and AngII plasma levels prior to treatment. The long-term decrease in systemic blood pressure observed in hypertensive individuals treated with ACE inhibitors is accompanied by a leftward shift in the renal pressure–natriuresis curve (see Figure 26–6) and a reduction in total peripheral resistance in which there is variable participation by different vascular beds. The kidney is a notable exception: because the renal vessels are extremely sensitive to the vasoconstrictor actions of AngII, ACE inhibitors increase renal blood flow via vasodilation of the afferent and efferent arterioles. Increased renal blood flow occurs without an increase in GFR; thus, the filtration fraction is reduced.
ACE inhibitors cause systemic arteriolar dilation and increase the compliance of large arteries, which contributes to a reduction of systolic pressure. Cardiac function in patients with uncomplicated hypertension generally is little changed, although stroke volume and cardiac output may increase slightly with sustained treatment. Baroreceptor function and cardiovascular reflexes are not compromised, and responses to postural changes and exercise are little impaired. Even when a substantial lowering of blood pressure is achieved, heart rate and concentrations of catecholamines in plasma generally increase only slightly, if at all. This perhaps reflects an alteration of baroreceptor function with increased arterial compliance and the loss of the normal tonic influence of AngII on the sympathetic nervous system.
Aldosterone secretion is reduced, but not seriously impaired, by ACE inhibitors. Aldosterone secretion is maintained at adequate levels by other steroidogenic stimuli, such as ACTH and K+. Excessive retention of K+ is encountered in patients taking supplemental K+, in patients with renal impairment, or in patients taking other medications that reduce K+ excretion.
ACE inhibitors alone normalize blood pressure in ~50% of patients with mild to moderate hypertension. Ninety percent of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a Ca2+ channel blocker, a β adrenergic receptor blocker, or a diuretic. Several ACE inhibitors are marketed in fixed-dose combinations with a thiazide diuretic or Ca2+ channel blocker for the management of hypertension.
ACE Inhibitors in Left Ventricular Systolic Dysfunction. Unless contraindicated, ACE inhibitors should be given to patients with impaired left ventricular systolic function whether or not they have symptoms of overt heart failure (see Chapter 28). Inhibition of ACE in patients with systolic dysfunction prevents or delays the progression of heart failure, decreases the incidence of sudden death and myocardial infarction, decreases hospitalization, and improves quality of life. Inhibition of ACE commonly reduces afterload and systolic wall stress, and both cardiac output and cardiac index increase. In systolic dysfunction, AngII decreases arterial compliance, and this is reversed by ACE inhibition. Heart rate generally is reduced. Systemic blood pressure falls, sometimes steeply at the outset, but tends to return toward initial levels. Renovascular resistance falls sharply, and renal blood flow increases. Natriuresis occurs as a result of the improved renal hemodynamics, the reduced stimulus to the secretion of aldosterone by AngII, and the diminished direct effects of AngII on the kidney. The excess volume of body fluids contracts, which reduces venous return to the right side of the heart. A further reduction results from venodilation and an increased capacity of the venous bed.
The response to ACE inhibitors also involves reductions of pulmonary arterial pressure, pulmonary capillary wedge pressure, and left atrial and left ventricular filling volumes and pressures. The better hemodynamic performance results in increased exercise tolerance and suppression of the sympathetic nervous system. Cerebral and coronary blood flows usually are well maintained, even when systemic blood pressure is reduced. In heart failure, ACE inhibitors reduce ventricular dilation and tend to restore the heart to its normal elliptical shape. ACE inhibitors may reverse ventricular remodeling via changes in preload/afterload, by preventing the growth effects of AngII on myocytes, and by attenuating cardiac fibrosis induced by AngII and aldosterone.
ACE Inhibitors in Acute Myocardial Infarction. The beneficial effects of ACE inhibitors in acute myocardial infarction are particularly large in hypertensive and diabetic patients (see Chapter 27). Unless contraindicated (e.g., cardiogenic shock or severe hypotension), ACE inhibitors should be started immediately during the acute phase of myocardial infarction and can be administered along with thrombolytics, aspirin, and β adrenergic receptor antagonists. In high-risk patients (e.g., large infarct, systolic ventricular dysfunction), ACE inhibition should be continued long term.
ACE Inhibitors in Patients Who Are at High Risk of Cardiovascular Events. Patients at high risk of cardiovascular events benefit considerably from treatment with ACE inhibitors. ACE inhibition significantly decreases the rates of myocardial infarction, stroke, and death. In patients with coronary artery disease but without heart failure, ACE inhibition reduces cardiovascular disease death and myocardial infarction.
ACE Inhibitors in Diabetes Mellitus and Renal Failure. Diabetes mellitus is the leading cause of renal disease. In patients with type 1 diabetes mellitus and diabetic nephropathy, captopril prevents or delays the progression of renal disease. Renoprotection in type 1 diabetes, as defined by changes in albumin excretion, also is observed with lisinopril. The renoprotective effects of ACE inhibitors in type 1 diabetes are in part independent of blood pressure reduction. In addition, ACE inhibitors may decrease retinopathy progression in type 1 diabetics and attenuate the progression of renal insufficiency in patients with a variety of non-diabetic nephropathies.
Several mechanisms participate in the renal protection afforded by ACE inhibitors. Increased glomerular capillary pressure induces glomerular injury, and ACE inhibitors reduce this parameter both by decreasing arterial blood pressure and by dilating renal efferent arterioles. ACE inhibitors increase the permeability selectivity of the filtering membrane, thereby diminishing exposure of the mesangium to peptide and protein factors that may stimulate mesangial cell proliferation and matrix production, 2 processes that contribute to expansion of the mesangium in diabetic nephropathy. Because AngII is a growth factor, reductions in the intrarenal levels of AngII may further attenuate mesangial cell growth and matrix production.
In general, ACE inhibitors are well tolerated. The drugs do not alter plasma concentrations of uric acid or Ca2+ and may improve insulin sensitivity in patients with insulin resistance and decrease cholesterol and lipoprotein (a) levels in proteinuric renal disease.
Hypotension. A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA. Care should be exercised in patients who are salt depleted, are on multiple antihypertensive drugs, or who have congestive heart failure.
Cough. In 5-20% of patients, ACE inhibitors induce a bothersome, dry cough mediated by the accumulation in the lungs of bradykinin, substance P, and/or prostaglandins. Thromboxane antagonism, aspirin, and iron supplementation reduce cough induced by ACE inhibitors. ACE dose reduction or switching to an ARB is sometimes effective. Once ACE inhibitors are stopped, the cough disappears, usually within 4 days.
Hyperkalemia. ACE inhibitors may cause hyperkalemia in patients with renal insufficiency or diabetes or in patients taking K+-sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.
Acute Renal Failure. Inhibition of ACE can induce acute renal insufficiency in patients with bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure, or volume depletion owing to diarrhea or diuretics.
Fetopathic Potential. The fetopathic effects may be due in part to fetal hypotension. Once pregnancy is diagnosed, use of ACE inhibitors must be discontinued immediately.
Skin Rash. ACE inhibitors occasionally cause a maculopapular rash that may itch, but that may resolve spontaneously or with antihistamines.
Angioedema. In 0.1-0.5% of patients, ACE inhibitors induce a rapid swelling in the nose, throat, mouth, glottis, larynx, lips, and/or tongue. Once ACE inhibitors are stopped, angioedema disappears within hours; meanwhile, the patient's airway should be protected, and if necessary, epinephrine, an antihistamine, and/or a glucocorticoid should be administered. Although rare, angioedema of the intestine (visceral angioedema) characterized by emesis, watery diarrhea, and abdominal pain also has been reported.
Other Side Effects. Extremely rare but reversible side effects include dysgeusia (an alteration in or loss of taste), neutropenia (symptoms include sore throat and fever), glycosuria (spillage of glucose into the urine in the absence of hyperglycemia), and hepatotoxicity.
Drug Interactions. Antacids may reduce the bioavailability of ACE inhibitors; capsaicin may worsen ACE inhibitor–induced cough; NSAIDs, including aspirin, may reduce the antihypertensive response to ACE inhibitors; and K+-sparing diuretics and K+ supplements may exacerbate ACE inhibitor–induced hyperkalemia. ACE inhibitors may increase plasma levels of digoxin and lithium and may increase hypersensitivity reactions to allopurinol.
PHARMACOLOGICAL EFFECTS. The AngII receptor blockers bind to the AT1 receptor with high affinity and show >10,000-fold selectivity for the AT1 receptor over the AT2receptor. Although binding of ARBs to the AT1 receptor is competitive, the inhibition by ARBs of biological responses to AngII often is insurmountable (the maximal response to AngII cannot be restored in the presence of the ARB regardless of the concentration of AngII added to the experimental preparation).
ARBs inhibit most of the biological effects of AngII which include AngII–induced: (1) contraction of vascular smooth muscle, (2) rapid pressor responses, (3) slow pressor responses, (4) thirst, (5) vasopressin release, (6) aldosterone secretion, (7) release of adrenal catecholamines, (8) enhancement of noradrenergic neurotransmission, (9) increases in sympathetic tone, (10) changes in renal function, and (11) cellular hypertrophy and hyperplasia.
Do ARBs have therapeutic efficacy equivalent to that of ACE inhibitors? Although both classes of drugs block the RAS, they differ in several important aspects:
• ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors. ACE inhibitors do not inhibit alternative non-ACE AngII-generating pathways. ARBs block the actions of AngII via the AT1 receptor regardless of the biochemical pathway leading to AngII formation.
• ARBs permit activation of AT2 receptors. Both ACE inhibitors and ARBs stimulate renin release; however, with ARBs, this translates into a several-fold increase in circulating levels of AngII. Because ARBs block AT1 receptors, this increased level of AngII is available to activate AT2 receptors.
• ACE inhibitors may increase Ang(1-7) levels more than do ARBs. ACE is involved in the clearance of Ang(1-7), so inhibition of ACE may increase Ang(1-7) levels more so than do ARBs.
• ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin and Ac-SDKP.
Whether the pharmacological differences between ARBs and ACE inhibitors result in significant differences in therapeutic outcomes is an open question.
Oral bioavailability of ARBs generally is modest (<50%, except for irbesartan, 70%), and protein binding is high (>90%).
Candesartan Cilexetil (ATACAND). Candesartan cilexetil is an inactive ester prodrug that is completely hydrolyzed to the active form, candesartan, during absorption from the GI tract. Plasma t1/2 is ~9 h. Plasma clearance of candesartan is due to renal elimination (33%) and biliary excretion (67%). The plasma clearance of candesartan is affected by renal insufficiency but not by mild-to-moderate hepatic insufficiency. Candesartan cilexetil should be administered orally once or twice daily for a total daily dose of 4-32 mg.
Eprosartan (TEVETEN). Peak plasma levels are obtained 1-2 h after oral administration, and the plasma t1/2 is 5-9 h. Eprosartan is metabolized in part to the glucuronide conjugate. Clearance is by renal elimination and biliary excretion. The plasma clearance of eprosartan is affected by both renal insufficiency and hepatic insufficiency. The recommended dosage of eprosartan is 400-800 mg/day in 1 or 2 doses.
Irbesartan (AVAPRO). The plasma t1/2 is 11-15 h. Irbesartan is metabolized in part to the glucuronide conjugate; the parent compound and its glucuronide conjugate are cleared by renal elimination (20%) and biliary excretion (80%). The plasma clearance of irbesartan is unaffected by either renal or mild-to-moderate hepatic insufficiency. The oral dosage of irbesartan is 150-300 mg once daily.
Losartan (COZAAR). Approximately 14% of an oral dose of losartan is converted by CYP2C9 and CYP3A4 to the 5-carboxylic acid metabolite EXP 3174, which is more potent than losartan as an AT1receptor antagonist. Plasma half-lives of losartan and EXP 3174 are 2.5 and 6-9 h, respectively. The plasma clearances of losartan and EXP 3174 are due to renal clearance and hepatic clearance (metabolism and biliary excretion) and are affected by hepatic but not renal insufficiency. Losartan should be administered orally once or twice daily for a total daily dose of 25-00 mg. Losartan is a competitive antagonist of the thromboxane A2 receptor and attenuates platelet aggregation. Also, EXP 3179, a metabolite of losartan without angiotensin receptor effects, reduces COX-2 mRNA upregulation and COX-dependent prostaglandin generation.
Olmesartan Medoxomil (BENICAR). Olmesartan medoxomil is an inactive ester prodrug that is completely hydrolyzed to the active form, olmesartan, during absorption from the gastrointestinal tract. The plasma t1/2 is 10-15 h. Plasma clearance of olmesartan is due to both renal elimination and biliary excretion. Although renal impairment and hepatic disease decrease the plasma clearance of olmesartan, no dose adjustment is required in patients with mild-to-moderate renal or hepatic impairment. The oral dosage of olmesartan medoxomil is 20-40 mg once daily.
Telmisartan (MICARDIS). The plasma t1/2 is ~24 h. Telmisartan is cleared from the circulation mainly by biliary secretion of intact drug. The plasma clearance of telmisartan is affected by hepatic but not renal insufficiency. The recommended oral dosage of telmisartan is 40-80 mg once daily.
Valsartan (DIOVAN). The plasma t1/2 is ~9 h. Food markedly decreases absorption. Valsartan is cleared from the circulation by the liver (~70% of total clearance). The plasma clearance of valsartan is affected by hepatic but not renal insufficiency. The oral dosage of valsartan is 80-320 mg once daily.
Azilsartan Medoxomil (EDARBI) is a prodrug that is hydrolyzed in the GI tract to the active drug azilsartan. The drug is available in 40 mg and 80 mg once-daily doses. The bioavailability of azilsartan is ~60% and is not affected by food. The elimination t1/2 is ~11 h. Azilsartan is metabolized mostly by CYP2C9 into inactive metabolites. Elimination of the drug is 55% in feces and 42% in urine. No dose adjustments are necessary for elderly patients or patients with renal impairment or mild to moderate hepatic impairment. The recommended dose is 80 mg once a day. Fixed–doses of azilsartan medoxomil with the diuretic chlorthalidone (EDARBYCLOR) are available as 40/12.5 mg and 40/25 mg once-daily single tablets.
Therapeutic Uses of AngII Receptor Antagonists. All ARBs are approved for the treatment of hypertension. In addition, irbesartan and losartan are approved for diabetic nephropathy, losartan is approved for stroke prophylaxis, and valsartan is approved for heart failure and to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction. The efficacy of ARBs in lowering blood pressure is comparable with that of ACE inhibitors and other established antihypertensive drugs, with a favorable adverse-effect profile. ARBs also are available as fixed-dose combinations with hydrochlorothiazide or amlodipine (see Chapters 27 and 28).
Current recommendations are to use ACE inhibitors as first-line agents for the treatment of heart failure and to reserve ARBs for treatment of heart failure in patients who cannot tolerate or have an unsatisfactory response to ACE inhibitors. There is conflicting evidence regarding the advisability of combining an ARB and an ACE inhibitor in heart failure patients.
ARBs are renoprotective in type 2 diabetes mellitus, in part via blood pressure–independent mechanisms. Many experts now consider them the drugs of choice for renoprotection in diabetic patients.
Adverse Effects. ARBs are well tolerated. The incidence of angioedema and cough with ARBs is less than that with ACE inhibitors. ARBs have teratogenic potential and should be discontinued in pregnancy. In patients whose arterial blood pressure or renal function is highly dependent on the RAS (e.g., renal artery stenosis), ARBs can cause hypotension, oliguria, progressive azotemia, or acute renal failure. ARBs may cause hyperkalemia in patients with renal disease or in patients taking K+ supplements or K+-sparing diuretics. There are rare reports of anaphylaxis, abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, pruritus, urticaria, hyponatremia, alopecia, and vasculitis, including Henoch-Schönlein purpura.
DRIs are a new class of antihypertensive drugs that inhibit the RAS at the level of the rate limiting step, renin. Angiotensinogen is the only specific substrate for renin, and its conversion to AngI presents a rate-limiting step for the generation of angiotensin peptides. Aliskiren hemifumarate (TEKTURNA) is the only DRI approved for clinical use.
Pharmacological Effects. Aliskiren is a low-molecular-weight non-peptide that is a potent competitive inhibitor of renin. It binds the active site of renin to block conversion of angiotensinogen to AngI, thus reducing the consequent production of AngII (see Figure 26–4). Aliskiren has a 10,000-fold higher affinity to renin (IC50 ~0.6 nM) than to any other aspartic peptidases. In healthy volunteers, aliskiren (40-640 mg/day) induces a dose-dependent decrease in blood pressure, reduces PRA and AngI and AngII levels, but increases plasma renin concentration by 16- to 34-fold due to the loss of the short-loop negative feedback by AngII. Aliskiren also decreases plasma and urinary aldosterone levels and enhances natriuresis.
Clinical Pharmacology. Aliskiren is recommended as a single oral dose of 150 or 300 mg/day. Bioavailability is low (~2.5%), but its high affinity and potency compensate for the low bioavailability. Peak plasma concentrations are reached within 3-6 h. The t1/2 is 20-45 h; steady-state plasma level is achieved in 5-8 days. Aliskiren is a substrate for P-glycoprotein (Pgp), which accounts for low absorption. Fatty meals significantly decrease the absorption of aliskiren. Elimination is mostly as unchanged drug in feces. About 25% of the absorbed dose appears in the urine as parent drug. Aliskiren is well tolerated in the elderly population, in patients with hepatic disease and renal insufficiency, and in patients with type 2 diabetes.
Therapeutic Uses of Aliskiren in Hypertension. Aliskiren is an effective antihypertensive agent that induces significant dose-dependent (75-300 mg) reductions in blood pressure. Aliskiren is as effective as ACE inhibitors (ramipril), ARBs (losartan, irbesartan, valsartan), and hydrochlorothiazide (HCTZ) in lowering blood pressure in patients with mild-to-moderate hypertension. Aliskiren also is as effective as lisinopril in lowering blood pressure in patients with severe hypertension. The long t1/2 of aliskiren allows its antihypertensive effects to be sustained for several days following termination of therapy.
Several studies indicate that the effect of aliskiren in combination with ACE inhibitors, ARBs, and HCTZ is additive in lowering systolic and diastolic blood pressure than any of the drugs alone. PRA is inhibited by aliskiren but significantly elevated with ramipril, irbesartan, and HCTZ (see Table 26–1). Coadministration of aliskiren with ramipril, irbesartan, or HCTZ neutralizes the increase in PRA to baseline levels. Because plasma renin levels correlate with the capacity to generate AngII, the ability of aliskiren to neutralize plasma renin in combination therapy may contribute to better control of blood pressure than monotherapy. Combination therapy of aliskiren with ACE inhibitors or ARBs is contraindicated in patients with diabetes or kidney impairment. Fixed-dose combinations of aliskiren/HCTZ (TEKTURNAHCT), aliskiren and the Ca++ channel blocker amlodipine besylate (TEKAMLO) and aliskiren/HCTZ/amlodipine besylate (AMTURNIDE) are available for antihypertensive therapy.
Aliskiren is an effective antihypertensive agent that is well tolerated in monotherapy and combination therapy. It has cardioprotective and renoprotective effects in combination therapy The ability of aliskiren to inhibit the increased PRA caused by ACE inhibitors and ARBs theoretically provides a more comprehensive blockade of the RAS and may limit activation of the local (tissue) RAS (see Table 26–1). Studies are ongoing to address whether aliskiren provides long-term advantages against end-organ damage in cardiovascular disease.
Aliskiren is currently recommended in patients who are intolerant to other antihypertensive therapies or for use in combination with other drugs for further blood pressure control.
Adverse Events. Aliskiren is well tolerated, and adverse events are mild or comparable to placebo with no gender difference. Adverse effects include mild gastrointestinal symptoms such as diarrhea observed at high doses (600 mg daily), abdominal pain, dyspepsia, and gastroesophageal reflux; headache; nasopharyngitis; dizziness; fatigue; upper respiratory tract infection; back pain; angioedema; and cough (much less common than with ACE inhibitors). Other adverse effects reported for aliskiren that were slightly increased compared with placebo include rash, hypotension, hyperkalemia in diabetics on combination therapy, elevated uric acid, renal stones, and gout. Like other RAS inhibitors, aliskiren is not recommended in pregnancy.
Drug Interactions. Aliskiren does not interact with drugs that interact with CYPs. Aliskiren reduces absorption of furosemide by 50%. Irbesartan reduces the Cmax of aliskiren by 50%. Aliskiren plasma levels are increased by drugs, such as ketoconazole, atorvastatin, and cyclosporine, that inhibit P-glycoprotein.
The RAS responds to alterations in blood pressure with compensatory changes (see Figure 26–2). Thus, pharmacological agents that lower blood pressure will alter the feedback loops that regulate the RAS and cause changes in the levels and activities of the system's components. These changes are summarized in Table 26–1.


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IIRC, Obama wasn't even tenure track; he was only an adjunct professor. (Which means hired by the year, or by the semester. A fill-in professor, till they can afford a full-timer. Distinguished position, eh?)
obamatollah was NOT even an adjunct professor.
he was a "visiting lecturer".
I have been an adjunct professor at local university...and, if I may say, far more intelligent than that marxist-muslime.

subset: commoncrawl


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The Sultan Abdülaziz Imperial Hunting Lodge was built in the second half of 19th century in a neoclassical European oriented style, during the construction of the Anatolian-Balkan Railway. It is referred to as 'Sultan Abdülaziz Sarayı' (= Palace of Sultan Abdülaziz), 'Av Kasrı' (= Hunting Lodge), 'Hünkâr Köşkü' (= the Ruler's cottage) or 'Kasr-ı Hümayun' (= Imperial Lodge).Due to its location above the Izmit Gulf, it has become one of the most important elements of the urbanscape.After the Turkish republic was established, the lodge has been used as the centre of local government and then as a museum. It has been affected by a number of major earthquakes and following its latest restoration in 1998, it suffered great damage during the Kocaeli/Gölcük earthquake of August 17, 1999.The damage was further aggravated as the building had not been well maintained, had been the subject of inappropriate repair interventions and left exposed to the effects of climatic conditions.Correspondent: J.M.Criel, Antwerpen.Sources: Yegan KAHYA (Istanbul Technical University, Faculty of Architecture).& Website of 'Art Nicomedia Derneği'.
For any use: see my Profile. NOTE: Many of my pictures are in sub-galleries (some within another, their name is in bold print)!


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Palm Bay (Fla.) Bayside offensive tackle Robert Lindsey landed his first offer earlier this week.
"FIU offered me earlier this week," Lindsey said. "I talked to Coach (Mario) Cristobal and their offensive line coach (Alex Mirabal)."
The 6-foot-4, 263-pound lineman talked about what he heard from Coach Mirabal during their conversation.
Article Continues Below
"He said that I have the spark that they wanted," Lindsey said. "He told me that I would be a good fit for them. He then gave me the verbal offer."
Lindsey is familiar with Florida International, as he made his way down to their campus this past summer.
"I went down there last year for their offensive line camp," Lindsey said. "It was a nice facility. I liked the coaches. They were teaching good technique."
He intends to return to the campus in the near future.
"I am planning to go to the junior day on March 24th," Lindsey said.
The next time he visits the Golden Panthers, he has some questions for them.
"I want to talk to them about their majors and how I can help their team," Lindsey said.
Lindsey indicated he wants to study business management.
He also reports interest from Georgia Tech, Illinois State, Iowa State, and Nevada. He will take a visit to Nevada at the end of March. At this stage, he doesn't claim a leader.


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As per Bylaw C-2 which regulates the collection of waste, residents must ensure that their garbage is placed at curbside no earlier than 6 p.m. on the day before the scheduled day of collection, and no later than 4 a.m. the scheduled day of collection.
During special collections, you can put your garbage at curbside a few days before the scheduled pick-up.
Information: 877.7990
3-Stream Program
The City of Dieppe follows the 3-Stream Program. The program involves the separation of recyclable waste, which is placed in transparent blue bags, organics waste, which is placed in transparent green bags and garbage, which is placed in transparent clear bags. To find out which bag in which to place your garbage, consult the Southeast regional service commission who is responsible for managing the area's solid waste or eco360.ca
The green bag is collected weekly, whereas the blue bag and the clear bag are collected in alternation of one week out of two.
Recyclables are sorted into more than 30 types of recyclable material. Compostable material from the green bags is processed and turned into a rich compost ideal for lawns and gardens.
Regular residential garbage pickup
|The collection of residential garbage in Dieppe takes place three days per week:
Collection schedule
To consult the collection schedule and find out which bag will be picked up this week, click here
Special Spring/Fall/Christmas tree garbage pickup
Special collection
Twice per year, a special collection is held in order to gather large items that are not picked up during regular collections, such as furniture, appliances, branches, etc.
Leaves picked up in yards must be placed in green bags for garbage collection.
Items should not be placed at the curbside or roadside more than seven days before the scheduled special collection.
Please note:
Domestic hazardous waste
Domestic hazardous waste from households only, such as cleaning products, chemical fertilizers, paint, razor blades, batteries, etc., may be dropped off free of charge at the RecycleSENB mobile unit during Hazardous Household Waste Day. You may also deposit these free of charge at the RecycleSENB facility at any time.
Hazardous Household Waste Day will be held on Saturday, October 21, between 9 a.m. and 2 p.m. The Mobile Unit will pick up your hazardous waste, free of charge, in the parking lot of the Dieppe Operations Centre located at 100 Rufin Street.
Visit eco360.ca for the hazardous domestic waste list.
Please note:
Mobile Eco-Depot
The Mobile Eco-Depot visits the Dieppe Operations Centre (100 Rufin Street) several times throughout the year.
The next visit will be held on October 25 and 26 between noon and 8 p.m.
Consult Eco 360's website for upcoming dates and the list of acceptable household waste.


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Separate names with a comma.
Posted By Don2222,
Oct 18, 2012 at 10:13 AM
He is not just blowing smoke up his A$$. LOL
Ummm...I really don't know what to say.
How about saying. On a few splits, It takes you where you want to go and keeps your butt from getting cold!
Well I wouldn't be setting my delicate parts that close to a fire & steam bomb on a moving bike, but I do think it's pretty awesome!
A neat idea but I would want that firebox located in the rear rather than under me. Also needs some refining as it appears to not have much power. Power output about the same as I give....
Hmmm....Needs "Old 97" painted on the side.
So you mean to tell me I can power all aspects of my life with firewood? More scrounging!
dammit, this is giving me some idears.....
Wife ain't gonna like 'em, either!!
Gives a new meaning to a weiner roast.
It's geared too high, but it's really neat!
I wouldn't be putting the fire and boiler near my delicate bits, either!
Nothing like a steam bomb under your butt ! I must say it would be fun to ride around if it had more zip and less whistle to it. Besides all the chicks dig a biker !
It all boils down to whether it is reliable or not.
All together now, "Bang bang chitty chitty bang bang our fine four fendered friend, ...
Don't know how to post a video, but here's the link:
The noise kinda reminded me of this.
Pun intended?
The most impracticle thing I think I've ever seen.
Probably EMP proof at least...
Funny how, when we see something on here, we just HAVE to look for more...
found this one on the 'Tube, pretty cool machine!
I can roll down hill too and without running a stop sign !


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You might think it's really hard to learn Chinese. You might think it's really hard to understand Chinese people and its culture. You might on the edge of
giving up learning Chinese.
Well, don't do that!!!
Maybe I can help!
Daisy's Mandrine Private Class: 40 RMB/ class.(50 minutes)
Here is something about me.
Name: Zhang Wei (Daisy)
Age: 22
University: Communication University of China (Chao Yang)
Major: English & Advertising
Chinese level: Native speaker; perfect mandrine; know a lot about Chinese culture.
English level: fluent in both oral and writen English.
If you want to know more about it, or have any question, email me at firstname.lastname@example.com.


text:
Monarch mirror roller help
A quick learner from USA says:
May 16, 2016
I have Monarch rolling mirror doors. What do you recommend to fix my chewed-up rollers?
Paul from SWISCO responded:
May 18, 2016
Check out our 23-028, this could work. Just make sure the measurements and style match up.


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VideoHive Total Redial Movie Trailer Titles 2574609
After Effects Project \ Titles \ 3D Object
After Effects Project - Total Redial Movie Trailer Titles 2574609 by Ninjamation @ VideoHive
After Effects Project \ Titles \ 3D Object
After Effects Version: CS3, CS4, CS5; File Size: 206mb; Requires Plugins: No; Resolution: 1920x1080.
Total Redial Movie Trailer Titles is an After Effects project perfect for your fast action, high intensity movie trailers, promos, or motion graphics. If you are looking for a project that is fast to build, and fast to render, this is the template for you.
3D Text version using Cinema 4d is coming soon.
- No Plug-ins needed
- Unlimited titles in any order you want
- Easily add text, colorize, and make your project to the timing you want
- Fast to build fast to render
- Full HD 1920 ×1080
- Includes video tutorials to get you going, and to show you the more advance settings
The music is not included, but contact this Audio Jungle user if you like it: http://bit.ly/MTYSDZ
Footage is not included
Thanks for looking! Please let me know if you have any questions.
Keywords: 3d, action, after effects, blue, film, flare, metal, movie, new, reboot, recall, text, title, total, trailer.


text: I have finally switched to steel wheels. One of the alloy wheels (out of the four) is still decent though I haven't checked the balancing lately. I can give this and four logos - together for 1500. Or get only the logos for Rs. 400. The chrome finish on the logo is almost half worn out (more greyish than shining chrome) though logo is still intact.


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Hey. I'm looking for a really good 16-oz thermos for coffee. Some looking online suggests that really good ones are the Thermos Nissan model, or the Zojorushi Tuff Slim.
But I haven't been able to find either of these anywhere inToronto. Anyone have suggestions of places that might carry them?
I'm mostly around downtown and Parkdale, but glad to go elsewhere if needed.
(Alternately - if anyone can recommend another really good 16 oz coffee thermos that you *can* find in town, let me know...)


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Homecoming: John La Farge Stained Glass Masterpieces Return to Boston
6:00pm Fri, Nov 22, 2013
Venue: The Cyclorama at the Boston Center for the Arts
539 Tremont Street, Boston, MA 02116
0 people saved this
The centerpiece of the entryway at this year's Boston International Fine Art Show (BIFAS) will be the our Special Exhibition, a John La Farge (1835-1910) stained glass triptych, circa 1889, saved and donated to Boston College by William and Alison Vareika. In addition to the exhibition, guests can hear presentations from William Vareika of William Vareika Fine Arts; Roberto Rosa, Serpentino Stained Glass; and Nancy Netzer, Director, McMullen Museum of Art, Boston College. This lecture is a part of the BIFAS Special Programs series and is complimentary with purchase of a ticket to the show, $15.
Trustees Literary Trail
In addition to the miles of beautiful wooded trails, open beaches, and green pastures found...
Search All Listings Here.


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The Pour House & The Art of Cool Project Present:
Rebirth Brass Band
The Hot At Nights
The Pour House Music Hall
224 S. Blount
Raleigh, NC, 27601
Doors 8:00 PM / Show 9:00 PM
This event is all ages
Watch & Listen
Whether seen on HBO's Treme or at their legendary Tuesday night gig at The Maple Leaf, Grammy-winning Rebirth Brass Band is a true New Orleans institution. Formed in 1983 by the Frazier brothers, the band has evolved from playing the streets of the French Quarter to playing festivals and stages all over the world. While committed to upholding the tradition of brass bands, they've also extended themselves into the realms of funk and hip-hop to create their signature sound. "Rebirth can be precise whenever it wants to," says The New York Times, "but it's more like a party than a machine. It's a working model of the New Orleans musical ethos: as long as everybody knows what they're doing, anyone can cut loose." In the wake of the sometimes- stringent competition amongst New Orleans brass bands, Rebirth is the undisputed leader of the pack, and they show no signs of slowing down.
The Hot At Nights
For fans of The Bad Plus and Charlie Hunter.
Says one Carolina newbie to one Carolina native, "Dang! I knew it would be hot in the Summer down here, but I had no idea that it would get even hotter at night!!" Meteorologically speaking, there is a scientific explanation for this phenomenon. But as far as the Raleigh-based exploratory jazz trio called The Hot at Nights, there is no explanation for them. 8-string guitar virtuoso Chris Boerner leads the group, with Matt Douglas on sax/woodwinds and Nick Baglio on drums. The group melted together in Boerner's studio over the many sweltering evenings of Summer, 2010. Though largely improvisational, the group's compositions pull from contemporary songwriters, classic funk, pop, rock, and of course the electric avant garde stylings that have spanned the last 30 years of contemporary jazz. Complex rhythms can quickly transform into head-bobbing groove fare. Simple melodies coaxed by all three players can explode into cacophonous meteor showers at the drop of a dime. Their limits go as high as the stratosphere and deep into the Earth's mantle. Both of which keep them sweating... even after the sun goes down.
$15 online / $18 at the door
Upcoming Events
The Pour House Music Hall
- Sorry, there are currently no upcoming events.


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WP Google Maps Error
In order for your map to display, please make sure you insert your Google Maps JavaScript API key in the Maps->Settings->Advanced tab.
1294 Gladstone Ave.
Victoria, BC
please note all phone calls are returned within 24 hours.
Book your appointment via email: http://tonicspatique.com/contact/
Our hours are:
Sunday: Closed
Monday: 10-6
Tuesday: 10-6
Wednesday, Thursday: 10-6
Friday: 10-4
Saturday: 10-6
Please email us to confirm availability – drop-ins are sometimes available, but not guaranteed, so best to avoid disappointment.


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Devil May Cry Episode 3 English Subbed
You are watching Devil May Cry Episode 3 English Subbed from the Devil May Cry Anime Show. Watch or Download Devil May Cry Episode 3 MP4 English Sub and other episodes of Devil May Cry Streamed for Free.
"Not Love"
Stream Devil May Cry Episode 3
Episode Summary: The daughter of the mayor begins seeing a mysterious man. Under suspicion that the man is a devil in disguise, Dante is sent to investigate. Along the way, the man questions whether a human and a devil can ever be together, forcing Dante to recall the relationship between his human mother, Eva, and his father, the legendary dark knight, Sparda.


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With all the questions surrounding auto finance and the wholesale market, CarMax Inc. executives reassured analysts they're prepared to meet any challenges that arise.
The used-car superstore chain recently announced results for the quarter ended Feb. 28 that beat many expectations.
"We realize there's a lot of noise in the market," said CarMax CEO Bill Nash. "We're confident about the track that we're on."
Total used vehicle unit sales grew 13.4 percent and comparable store used unit sales rose 8.7 percent versus the prior year's same quarter. The comparable store sales performance resulted from a strong increase in conversion, together with a modest increase in store traffic.
Wholesale vehicle unit sales declined 1.2 percent versus the same period a year ago, as contributions from the growth in CarMax store base and an improved appraisal buy rate were more than offset by a reduction in appraisal traffic. In particular, age 7-to 9-year old wholesale vehicles continued to be in shorter supply.
Nash said some of that decline came from the delay in tax refunds.
Other sales and revenues increased 19.2 percent, primarily reflecting improvements in extended protection plan (EPP) revenues and net third-party finance fees. EPP revenues increased 19.3 percent, largely due to the growth in used unit sales and favorable adjustments to the reserve for cancellations. Net third-party finance fees improved by 44.4 percent as a result of more sales to consumers with higher credit scores.
Total gross profit increased 14.9 percent to $562.2 million. Used vehicle gross profit rose 14.7 percent, driven by the 13.4 percent increase in total used unit sales.
Used vehicle gross profit per unit was largely consistent at $2,134 versus $2,109 in the prior year period. Wholesale vehicle gross profit declined 7.8 percent versus the prior year's quarter, reflecting the 1.2 percent decline in wholesale unit sales and a decrease in wholesale vehicle gross profit per unit to $938 from $1,005.
Other gross profit increased 46.1 percent, primarily reflecting the improvement in EPP revenues and net third-party finance fees, as well as some favorable payroll-related cost experience in CarMax's service operations.
One of the biggest concerns going forward is the Increasing supply of used vehicles. Nash said this is a good situation for CarMax's business.
"We believe lower prices will be beneficial to sales as cars become affordable for our customers," Nash said.
He said the company has managed periods of sudden declines in wholesale values and high off-lease volumes in the past.


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Tag: streetart
Triple Play: Lister
Australian artist Anthony Lister's been very busy in the weeks leading up to his solo show at Jonathan LeVine Gallery, opening tomorrow night. It's been a while since we last featured him here, but I'm glad to report he's showing his former hometown some love by completing a number of murals in Brooklyn and Manhattan. Here are three of the
five seven he's done so far:
[Lister – all photos (c) Luna Park]
Lister is also the subject of the forthcoming Anthony Lister – Adventure Painter release from Gingko Press, authored by Roger Gastman and Tristan Manco.
Anthony Lister: Power Tripping
Jonathan LeVine Gallery
529 West 20th Street
9th Floor
New York, New York 10010
June 28—July 26, 2014
Opening: Saturday, June 28, 6—8pm
Triple Play: Chris Stain & Billy Mode
Artists Chris Stain and Billy Mode extended their long-standing collaboration to include 13 youths from creative-arts youth development organization Cre8tive YouTH*ink in their process. The result? Sign Language, a stunning mural on the side of 267 Pacific Street (at Smith Street), based on a photograph by legendary street photographer Martha Cooper.
Billy Mode has just dropped Omni, a series of small edition, hand-sprayed, hand-cut, multi-layer, stencil prints available via Freshly Baked.
[Chris Stain & Billy Mode for Cre8tive YouTH*ink, Bushwick Collective & Welling Court – all photos (c) Luna Park]
Fall Wheatpastes in Brooklyn
The last month has seen lots of new activity by old favorites. New wheatpastes have gone up in Brooklyn: Swoon and Over Under in Red Hook, ECB in Bushwick and Judith Supine in Williamsburg.
Aiko's Historic First on the Bowery/Houston Wall
Faile Take Manhattan
Brooklyn's own Faile are the latest to embellish the curated wall at the intersection of Houston and the Bowery. As noted by the L Magazine yesterday, this marks the duo's first, large-scale, outdoor installation in Manhattan since pasting the facade of 11 Spring five years ago.


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Nigerian banks key stocks to watch this week
by July 29, 2013 11:46 am0
Investors are expected to trade cautiously this week following the release of earnings particularly from banking heavyweights such as Guaranty Trust (GT) Bank, Zenith Bank and Access Bank.
"This week the markets may still be influenced by the outcome of the Monetary Policy Committee (MPC) last week, which increased the cash reserve ratio for the public sector fund from 12 per cent to 50 per cent. We are expecting the Federal Reserve Bank to meet on rate decisions, we don't expect anything different from what they had last time," FSDH Merchant Bank Limited Head of Research Ayodele Akinwunmi told CNBC Africa on Monday.
The outcome of the MPC meeting last week is expected to influence their results and market activity. Last week Nigeria's MPC kept its monetary policy rate at 12 per cent for the 11th time in a row.
"We don't expect so much growth in terms of earnings from these banks this year, looking at what they did last year, and the fact that yield on the securities have really gone down," Akinwunmi explained.
"This year we don't expect too much growth from them but then if you look at the current prices of these banks' ratios, they're actually undervalued but I think the current market sentiment may still prevail over earnings released this week."
Nigeria's largest cement manufacturing company Dangote Cement is one of the many stocks investors are expected to keep an eye on this week as their current earnings remain strong. Access Bank, Skye Bank, Diamond Bank, GT Bank and Zenith Bank are other key stocks for the week. Majority of these banks' stocks are currently trading below intrinsic value.
"Investors who a have medium to long term view should actually position [themselves] in these banking stocks and maybe towards the end of August and the last quarter of the year, I think they will likely reap good dividends and earnings," said Akinwunmi.


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Colours of the Night
- (Digipack Packaging)
- Artist: Peter Broderick
- Format: CD
- Release Date: 5/18/2015
|your cart is empty
Colours Of The Night, Peter Broderick's first full-length for Bella Union in three years, had a rather odd conception to say the least. The American born multi-instrumentalist and songwriter went along for the ride when invited for a so-called "recording residency" in the small town of Lucerne, Switzerland. Through several memorable concert evenings in the town on various tours, he developed a friendship with some of the locals, who eventually got the idea of inviting Broderick to be a guest of the city for three weeks while recording an album with a backing band of local musicians. All of which was to take place in the studio of Timo Keller, a local producer and engineer known primarily for his involvement in the Swiss hip-hop scene.
To play the media you will need to either update your browser to a recent version or update your version of Flash Player.


text: Toshiba LR44 AG13 Alkaline 1.5 Volt Batteries x20 Buy for $6.75 A battery designed by Japanese engineers, which meets the highest standards of modern button batteries. Has a very long shelf life, a wide range of safe operation temperatures and is resistant to leaking. Tags: lr44 battery, lr44 battery ag13, lr44 battery button cell, lr44 battery compatible, lr44 battery cross reference, lr44 battery equivalent, lr44 battery replacement, lr44 button battery, lr44 button battery cross reference, lr44 button cell, lr44 button cell batteries, lr44 button cell equivalent, lr44 button cell replacement, toshiba lr44 battery, toshiba lr44 battery cross reference, toshiba lr44 battery equivalent, toshiba lr44 battery equivalents, toshiba lr44 battery equivalents energizer, toshiba lr44 battery specifications


text:
Japan's Suzuki Motor Corp says its net profit nosedived by 91.8 per cent in the three months to June from a year-earlier because of weak sales and a stronger yen.
The manufacturer of small cars and motorcycles said its net profit came to Y2.1 billion yen ($A26.46 million) for the April-June quarter, down from 26.0 billion yen a year earlier.
Operating profit plunged 79.7 per cent to Y6.9 billion ($A86.93 million) as revenue fell 36.6 per cent to Y577.1 billion ($A7.27 billion) "due to a slump in sales at home and overseas as well as the appreciation of the yen," it said.
While suffering operating losses in the Japanese and North American markets, Suzuki enjoyed a 33.4 per cent gain in operating profit in Asia, notably in India, one of the world's fastest growing car markets.
Suzuki left its annual forecasts unchanged, projecting net profit of Y5 billion, operating profit of Y10 billion and revenue of Y2.3 trillion ($A28.98 billion).


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Kate B.
London, United Kingdom, SE10...
Joined on September, 2013
Gender: Female
Average Rating:
Weekdays after 7PM
Weekends at any time
Weekends at any time
Lives Near:
Can Meet:
Up to 20 minutes away for no additional charge
Up to 1 hour away for a flat fee
Up to 1 hour away for a flat fee
EducationBA (Hons) 2.1 in English Literature
A Levels in English Language (A), English Literature (A) and Theatre Studies (B)
ExperienceHi, I`m Kаte! I live with my lоng term pаrtner in Greenwich аnd during the week I wоrk аs а PA tо twо аctоrs аgents in centrаl Lоndоn.
Tо supplement my incоme I аm nоw lооking tо tutоr children in my bоrоugh оf Greenwich. My degree is in English sо this is predоminаntly where my knоwledge lies, аlthоugh fоr yоunger children I cоuld help with Mаths аs well.
I`m hаppy tо tutоr children оf аll аges I hаve previоusly run drаmа wоrkshоps in cоnjunctiоn with Greenwich Theаtre fоr primаry аged children аnd fоr mаny yeаrs аssisted in the running оf а Brоwnie Pаck in my hоmetоwn оf Sheffield.
Pleаse dоn`t hesitаte tо get in tоuch if yоu wоuld like аny mоre infоrmаtiоn preferаbly I wоuld wоrk frоm hоme (we live in а very sаfe аreа with а cоncierge аnd security cаmerаs) but I will cоnsider tutоring elsewhere аlsо.
HobbiesReading, writing, swimming and baking.
Inquire about this tutor
The tutor will respond if they are available/interested.


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Modern Diamond Shaped Crystal Hanukkah Menorah with Flat BaseProduct ID: MNR-KA-44527
Temporarily out of stock
Please contact us for additional information about this product
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Modern Diamond Shaped Crystal Hanukkah Menorah with Flat Base
A stunning contemporary flat based designed Hanukkah menorah made of crystal with diamond shaped candle cup holders.
Material Crystal
Dimensions 7x35cm
Estimated processing time: 2-4 Business Days.
Your order's processing time is the estimated number of days that it will take for your order to be prepared for shipment from our Israel-based fulfillment center.
Important Safety Instructions and Disclaimer Learn More
Modern Diamond Shaped Crystal Hanukkah Menorah with Flat Base
The flat base of this crystal menorah is sculpted to reflect light passing through it. Sparkling diamond shaped candle cup holders continue the modern design with the Shamash at the center. You will love how this menorah shines when lit and when retelling the story of Hanukkah one can appreciate old tradition mixed with modern lines.
Perfect as a gift for a loved one.


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Love and Racism (cartoon)
Kids don't start to hate until they learn to hate–often from the ones they love most. Don't spread ignorance and hatred, as we see in this cartoon it's an airborne … Continue reading
Cyber Baby – Future Soldier
Shel Silverstein said, "Never explain what you do. It speaks for itself. You only muddle it by talking about it." I try to stick to that, but I do want … Continue reading
Naughty Children, Then and Now
As seen on Yes! Magazine's website… More on Coal From PlanetSave: In Historic Reversal, US House of Representatives Cling to 20th Century Loyalty to Fossil Fuels — While Saudi Arabia … Continue reading
Hank D and the Bee: SNOW!
It's been a crazy winter, but we can still spend time outside. Did you hear me? Hey everyone, GO OUTSIDE!!! From Jennifer Lance and EcoChildsPlay: Play Outside! Free Range Kids … Continue reading


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Manet Load Balancing Parallel Routing Protocol
In recent years, multi-path routing protocols have attained more attention in mobile ad hoc networks as compared to other routing schemes due to their abilities and efficiency in improving bandwidth of communication, increasing delivery reliability, responding to congestion and heavy traffic. Several protocols have been developed to address multi path routing, but it always has a problem that the discovered paths may be not 100% disjoint and sending data is done in only one path until it's broken; the discovery of multiple paths also generates more overhead on the network. Load Balancing Parallel Routing Protocol [LBPRP] tried to solve previous multi path problems, distributing traffic among multiple paths) sending data in parallel form as it uses all paths in the same time.


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I've come to love an Irish breakfast: eggs, thick and meaty bacon, small delicious sasuages the size of my pinkie finger, grilled tomato, and thick brown Irish soda bread. Yvonne, the owner of Coolakay House and our host for the night, explained to us that her husband and several generations of his family were born on this farm. Her mother-in-law bakes the Irish brown soda bread for breakfast each day, and it was by far the best soda bread we've yet enjoyed. Their 19th century farmhouse is home to not only the B&B, but is also a working farm with sheep and cattle in the fields.
Well-fueled, we were ready to go when Kevin picked us up and dropped us off at the start of today's 19km walk.
The Wicklow Way is well-marked, but the detailed route description provided by Wonderful Ireland walking tours is priceless. We walked through pine forests which opened to amazing views of the Glencree Valley, Sugar Loaf mountain, and even the Irish Sea in the distance.
We walked the final three kilometers to the Wicklow Way Lodge, our B&B for the evening, on increasingly narrow country lanes that were lined on each side with stone walls overgrown with ivy and holly. As we crossed the River Avonmore on a stone bridge built in 1828, we saw an Irish family throwing sticks into the river for their Lab to fetch. As usual in Ireland, we struck up a conversation and learned that the wife had played basketball for the Irish national team and traveled to the Basketball Hall of Fame in Springfield, MA. Her daughter plays Gaelic football, sort of a cross between soccer and rugby and hugely popular in Ireland. Her team has been invited to play in Boston next year, and we chatted about travel, sports, and Irish connections around the world.
We kept our fingers crossed all day that it wouldn't rain while we were hiking, and we were actually rewarded with bright sunshine as we finished our walk at the beautiful B&B.
Our room is lovely, with wooden floors, a cathedral ceiling, and floor-to-ceiling windows that seem to attract the family's chickens. It's a comfortable spot to put up our feet and relax after 5 hours walking, and to rejuvenate before tomorrow's walk as we head into Glendalough.


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Top nearby In-Home Care Services
Reviews of Alternatives in Home Care | Home Care
Caring109837650 April 23, 2015
I am a current client of this provider
Very good care. Able to handle changes and requests in a timely manner.
Caring73585750 October 30, 2013
I am a current client of this provider
I liked Alternatives because they're willing to customize care to what you need. We've been using them for 4 to 6 weeks.They're willing to do a variety of things and they're really working to help engage the person. The caregiver is taking the time to build a relationship with my mom in law.
Write a Review
About Alternatives in Home Care
Alternatives in Home Care is an in-home care provider serving Tucson, AZ and the surrounding area. Alternatives in Home Care offers non-medical services in the home, such as meal preparation, housekeeping, and transportation. Contact the provider for more details on home care services and rates.
Features of Alternatives in Home Care
- German
- Spanish
- Hourly Rate: $18/Hour
Range of services
- Companion Care
- Personal Care Assistants
- Range Of Services Extra: Professional Care Management
Types of care
- Transportation: Yes
- Doctor Visit Companionship
- Light Housekeeping
- Transfer Assistance
- Dressing And Grooming
- Bathing And Toileting
- Exercise
- Finances Bookkeeping
- Home Maintenance
- Walking Wheelchair Assistance
- Memory Care
- Companionship
- Meal Preparation
- Errand And Grocery Assistance
- Travel Details: Staff Will Travel 30+ Miles To Provide Care
- In Person Interviews
- Reference Checks
- Driving Record Check
- Residency Confirmation
- Drug Screening
- Sex Offender Check
- Continual Training
Training Areas
- Patient Transfers
- Stress Management
- Family Communication
- Transition Issues
- Memory Care Training
- Ethics
- Validation Techniques
- Training Areas Extra: Infection Control, Client Confidentiality/Client Rights, Abuse & Neglect Prevention, Documentation & Recordkeeping
Payment options
- Insurance
- Check
Payment details
- Payroll Provided For Caregivers
- Bonded And Insured
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- Hiring a Caregiver for In-Home Help
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- Cost of In-Home Care by State
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- Medicare Coverage of Home Care
- Q&A: Does Medicaid Cover Long-Term In-Home Care?
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text: I was at the local mall this weekend. I usually stop by the phone stores to play. I was speaking with a rep at a verizon reseller and he mentioned that the 4 incredibles they got in all came with the extended battery and back cover. He pulled one out and he was not kidding. The phone did not have the standard battery or cover. It only came with the extended battery. Anyone else seen this?


text:
+31 (0)10 - 265 50 70
The GAI-Tronics 13380-005 is a 15Watt IEC and ATEX loudspeaker. The GAI-Tronics 15 Watt ATEX Speaker is available as 8 Ohm, 16 Ohm, 70v and 100v version. The speaker has a global weather rating of IP66 and Zone 1 approval to IEC, ATEX, INMETRO and GOST-R.
The GAI-Tronics 15 Watt speakers come in a red color and are available as an Exd and an Exde version on request.
Available models
Please contact us for more information.


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Aqua-Fit Algae Cleaner Pad for Glass Aquariums; Available in 2 sizes
Online Price $3.77Regular Price $3.97
This variant is currently sold out
The Aqua-Fit Algae Cleaner Pad for Glass Aquariums are designed to wipe away algae on the inside of your aquarium. One side has a rough scrubbing pad to get the stubborn algae, and the other side has a soft sponge. The small sponge is 7.25 cm x 7.25 cm, and the large sponge is 10 cm x 15 cm.
The sponge and scrubbing pad may vary in colour from the image shown.


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Kink Luton, Bedfordshire (Closed)
Welcome to Kink. In the past this club has been numerous different names, sexualities and colours. We are now Luton s Biggest gay bar/club but we are still a small but intermit club that is here for all! The newly refurbished club now includes a heated and partly covered balcony, sexy red and black chill out lounge, fully stocked bar, beautiful dance floor including a sexy pole for your amusement. With a selection of drink promotions such as our £1 kink Lager and our house double and mixer read more


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Register for this Event
Mark your calendars to join us on Tuesday, May 30, 2017 as de Bono Consulting and Resources Unlimited presents the third webinar in our de Bono Thinking Skills series. This is a FREE Webinar.
Marion Smith, a de Bono Master Trainer, will be presenting, "de Bono Thinking Systems Tools & DiSC: Facilitating Excellence in Communication and Performance"
We want to provide you with a solution that combines two methodologies: DiSC and de Bono Critical Thinking Tools including Six Thinking Hats and Lateral Thinking. This potent combination of using these methods together will give your organization the boost it needs to achieve its best results!