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Pulmonary intralobar arteries express heme oxygenase (HO)-1 and -2 and release carbon monoxide (CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development (0.77 ± 0.06 mN/mm) in pulmonary vascular rings treated with 15 μmol/l chromium mesoporphyrin (CrMP), an inhibitor of HO-dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO-2 antisense oligodeoxynucleotides (ODN), which decrease pulmonary HO-2 vascular expression and CO release. Hypoxia-induced contraction of vessels treated with CrMP is attenuated (P < 0.05) by endothelium removal, by CO (1–100 μmol/l) in the bathing buffer, and by endothelin-1 (ET-1) receptor blockade with L-754142 (10 μmol/l). CrMP increases ET-1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration-response curve to ET-1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP (40 μmol/kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET-1 receptor antagonist L-745142 (15 mg/kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia-induced pulmonary vasoconstriction by reducing ET-1 vascular levels and sensitivity.
- hypoxic pulmonary vasoconstriction
- heme oxygenase
arterial vessels generate carbon monoxide (CO) along with biliverdin via metabolism of heme by heme oxygenase (HO) isoforms -1 and -2 (36). Arterial vessels express HO-2 constitutively, whereas HO-1 is primarily expressed as the result of exposure to inducing factors or conditions (24, 30). Products of heme metabolism by HO possess biological activities that influence vascular functions. Biliverdin and its metabolic product bilirubin are antioxidants capable of preventing oxidant-induced microvascular leukocyte adhesion (6). CO stimulates soluble guanylate cyclase (19) and Ca2+-activated K+ (KCa) channels (10, 30) in vascular smooth muscle, interferes with the expression and release of endothelin-1 (ET-1) in endothelial cells (18), and inhibits endothelial nitric oxide synthase (27). CO of vascular origin attenuates vasoconstrictor responsiveness to myogenic stimuli in rat gracilis muscle arterioles (37) and to constrictor agonists in the rat renal interlobar arteries (10), the rat tail artery (30), and aorta (3). CO of vascular origin was also implicated in the mediation of dilatory responses to acetylcholine in porcine pulmonary arteries (35), to heme-l-lysinate in small rat mesenteric arteries (22), and to acute hypoxia in cerebral arteries of piglets (15).
Hypoxia causes constriction of pulmonary arterial vessels in vitro and in vivo (9, 14, 23, 38). The pulmonary vasoconstriction elicited by hypoxic conditions is attenuated by blockade of ET-1 subtype A (ETA) receptors, suggesting contribution of ET-1 to the mechanism underlying the constrictor response (9, 23). That HO-derived CO downregulates ET-1 expression and release in endothelial cells (18) raises the possibility that CO inhibits the ET-1-dependent component of the constrictor response to hypoxia in pulmonary vessels. However, the result of studies examining modulation of hypoxia-induced pulmonary vasoconstriction by CO is less than conclusive. Although exogenous CO dilates pulmonary vessels preconstricted with an agonist of thromboxane receptors (21), exogenous CO does not consistently elicit pulmonary vasodilation during hypoxic conditions (1, 28). While experimental interventions that enhance lung HO-1 expression prevent the pulmonary hypertension produced by chronic hypoxia in rats (4), the elevation of pulmonary arterial pressure produced by chronic hypoxia was similar in HO-1 null mice and the corresponding wild-type controls (33). In addition, the inhibitors of HO affect hypoxia-induced pulmonary vasoconstriction inconsistently, having little or no effect under basal conditions, while intensifying the response when nitric oxide synthesis is decreased (2).
The present study was designed to test the hypothesis that CO produced by pulmonary arterial vessels attenuates hypoxia-induced pulmonary vasoconstriction by interfering with the vascular formation or actions of ET-1. We conducted experiments in the small pulmonary arteries of rats for the following reasons: 1) to quantify the generation of CO and determine whether it is affected by acute hypoxia, 2) to examine the effect of interventions that decrease HO activity or expression on the vascular response to acute hypoxia, and 3) to determine the effect of HO inhibition on constrictor responsiveness to ET-1 and vascular ET-1 levels.
Chemicals. Chromium mesoporphyrin (CrMP) was purchased from Porphyrin Products (Logan, UT), and stock solutions were prepared in 50 mmol/l Na2CO3. CO was purchased from Tech Air (White Plains, NY), and CO-saturated solution (1 mmol/l) was prepared immediately before use (37). ET-1 was purchased from Bachem Bioscience (King of Prussia, PA). L-754142 was a gift from Merck Research Laboratories (Rahway, NJ).
Antisense (AS) oligodeoxynucleotides (ODN) complementary to rat HO-1 mRNA (HO-1 AS-ODN) and rat HO-2 mRNA (HO-2 AS-ODN) and the corresponding scrambled (S) ODN (HO-1 S-ODN and HO-2 S-ODN) were synthesized by Genosys Biotechnologies (Woodland, TX); each ODN was phosphorothioated on the first three bases of the 3′ end and was purified by high-pressure liquid chromatography. The sequence of HO-1 AS-ODN is 5′-GGCGCTCCATCGCGGGACTG-3′ and target bases +10 to –9 of HO-1 mRNA; the sequence of HO-2 AS-ODN is 5′-TCTGAAGACATTGTTGCTGA-3′ and targets bases +11 to –9 of HO-2 mRNA. The sequence of HO-1 S-ODN is 5′-TCCAGCGGCGTCAGCGGTGC-3′, and the sequence of HO-2 S-ODN is 5′-GATCTGACTTCAAGTGATTG-3′. The effectiveness of HO-1 AS-ODN and HO-2 AS-ODN to reduce tissue expression of HO-1 and HO-2, respectively, was documented previously (5, 10).
Animals. Experiments were conducted on male Sprague-Dawley rats (200–300 g; Charles River; Wilmington, MA) according to protocols approved by the Institutional Animal Care and Use Committee. In the experiments using isolated pulmonary vessels, the animals were anesthetized (60 mg/kg ip pentobarbital sodium), heparin (1,000 U/kg) was injected intravenously, and the lungs were removed. Immediately thereafter, the lungs were placed on a dish filled with ice-cold Krebs buffer composed of (in mmol/l) 118.5 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.2 MgSO4, 25.0 NaHCO3, and 11.1 dextrose, and pulmonary intralobar arteries (100–200 μm of internal diameter) were dissected out for use in vascular contractility studies and for assessment of HO isoform expression, CO production, and ET-1 levels. In some experiments, the animals were treated 24 h before experimentation with HO-1 AS-ODN, HO-2 AS-ODN, HO-1 S-ODN, or HO-2 S-ODN. The ODN were encapsulated in liposomes (1:1 molar ratio nucleotide/lipid) prepared using premixed 1,2-bis-(oleoyloxy)-3-(trimethylammonio)propane and l-a-dioleoyl phosphatidylethanolamine. The cationic lipid mixture and instructions for preparation of the lipid/oligomer complex were supplied by Avanti Polar Lipids (Alabaster, AL). Liposomes containing HO-1 AS-ODN, HO-2 AS-ODN, HO-1 S-ODN, or HO-2 S-ODN were suspended in 5% dextrose and injected (2 mg/kg) intravenously.
In studies examining the effect of hypoxia on pulmonary artery pressure (7), rats were anesthetized with Inactin (100 mg/kg ip), and cannulas were placed in the trachea, a femoral vein for drug administration, and in the pulmonary artery (via the right jugular vein and the right ventricle) for measurement and recording of pressure by means of a pressure transducer (model P23 ID, Statham Division, Gould; Oxnard, CA) coupled to a polygraph (model 7D, Grass Instruments; Quincy, MA).
Expression of HO-1 and HO-2 isoforms. HO-1 and HO-2 protein expression was assessed in isolated pulmonary intralobar arteries of rats treated 24 h earlier with HO-1 AS-ODN, HO-2 AS-ODN, HO-1 S-ODN, or HO-2 S-ODN. The tissues were homogenized, the homogenate was centrifuged at 10,000 g, and the supernatant was analyzed for HO-1 and HO-2 by immunoblotting as previously described (10). β-Actin was also assayed, the results taken as an index of the adequacy of sample loading.
Assessment of CO release from pulmonary arteries ex vivo. Segments of pulmonary intralobar arteries (∼4 segments 2 mm in length) were placed into amber glass vials (2 ml) containing 1.0 ml of Krebs buffer gassed with 95% O2-5% CO2 (Po2, 160 mmHg), or when so indicated 95% N2-5% CO2 (Po2, 15 mmHg). The vials were capped tightly with rubberized Teflon liners, and the samples were incubated for 60 min at 37°C. In a limited number of experiments, the HO inhibitor CrMP (15 μmol/l) was included in the buffer. The incubations were terminated by placement of the vials on ice. Subsequently, internal standards made of isotopically labeled CO (13C16O and 13C18O) were injected into samples and the CO content of the headspace gas was determined by gas chromatography/mass spectroscopy, as previously described (10, 37).
Assessment of vascular ET-1 levels. Segments of pulmonary intralobar arteries were placed inside glass vials containing Krebs buffer (1 ml) gassed with 95% O2-5% CO2 or 95% N2-5% CO2, the vials were capped, and the samples were incubated for 60 min at 37°C. When so noted, the incubations were conducted in buffer containing CrMP (15 μmol/l). At the conclusion of the incubation, the tissues were homogenized in 1 mol/l HCl containing 1% acetic acid, 1% trifluoroacetic acid, and 1% NaCl, and the resulting sample was processed (12) and assayed for ET-1 by radioimmunoassay using a commercially available kit (Peninsula Laboratories; San Carlos, CA).
Effect of hypoxia on isometric tension development in pulmonary intralobar arteries. Pulmonary arterial vessels with an internal diameter averaging 153 ± 12 μm were cut into ring segments 2 mm in length. The vascular rings were mounted on 25 μm stainless steel wires in the chambers of a multivessel myograph (J.P. Trading; Aarhus, Denmark) for measurement of isometric tension (38). The vessels were bathed in Krebs buffer maintained at 37°C and gassed with 95% O2-5% CO2, unless indicated otherwise. After an equilibration period (30 min), the vessels were stretched radially so that the internal circumference was equivalent to 90% of the vessel's normal size if relaxed under a transmural pressure of 17.5 mmHg (20), which approximates the mean pressure measured in the pulmonary artery of rats under normoxic conditions. Isometric tension was monitored continuously and was expressed as milliNewtons per millimeter of vessel length.
Experiments were initiated by exposing the vessels to Krebs buffer modified by increasing the concentration of KCl to 80 mmol/l (by equimolar exchange with NaCl) to ascertain reproducibility of contractile responses. Subsequently, the vessels were washed with unmodified Krebs buffer and allowed to rest for 30 min before hypoxic conditions were established by gassing the bathing buffer with 95% N2-5% CO2 and assessment of ensuing changes in isometric tension. The effect of hypoxia on isometric tension was investigated in pulmonary intralobar arteries taken from rats treated 24 h before experimentation with HO-1 AS-ODN, HO-2 AS-ODN, or the corresponding HO-1 S-ODN or HO-2 S-ODN. The effect of hypoxia also was examined in endothelium-intact and endothelium-denuded (38) pulmonary vessels from untreated normal rats, bathed in buffer containing and not containing the HO inhibitor CrMP (15 μmol/l). In these experiments, the effectiveness of the denudation procedure was ascertained by documenting that acetylcholine (10 μmol/l)-induced relaxation of denuded pulmonary vessels precontracted with PGF2α (10 μmol/l) was minimal (<10% of PGF2α-induced tone) relative to the response in endothelium intact vessels (>50% of PGF2α-induced tone). Additional studies (32), conducted in preparations bathed in buffer containing CrMP (15 μmol/l), compared the vascular response to hypoxia in vessels exposed and not exposed to exogenous CO (1–100 μmol/l), biliverdin (10 μmol/l), or to L-754142 (10 μmol/l), a nonselective antagonist of ET-1 receptors. The pulmonary vascular response to acute hypoxia in preparations treated and not treated with CrMP (15 μmol/l) was also examined after inclusion of 1.0 μmol/l PGF2α into the buffer, which elicited a modest elevation of isometric tension (from 0.36 ± 0.09 to 0.44 ± 0.09, n = 12; P < 0.05) believed to be a priming factor for expression of hypoxia-induced contraction of pulmonary arterial smooth muscle ex vivo (14).
Effect of HO inhibition of vascular responsiveness to ET-1. Ring segments of pulmonary intralobar arteries from normal rats were prepared for measurement of isometric tension. Concentration-response curves to ET-1 (10–12 – 5 × 10–7 mol/l) were constructed by increasing cumulatively the concentration of agonist every 3 min and recording the resulting changes in tension at the end of the 3-min period. The experiments were conducted in vessels bathed in buffer containing and not containing CrMP (15 μmol/l); contractile responses to ET-1 in CrMP-treated preparation also were examined after the addition of exogenous CO (1.0 μmol/l) to the buffer.
Effect of acute hypoxia on pulmonary artery pressure. Pulmonary artery pressure was monitored in instrumented rats during successive periods of ventilation with air and a hypoxic gas mixture (5% O2-5% CO2-90% N2). The effect of hypoxia also was examined after pretreatment with the HO inhibitor CrMP (40 μmol/kg iv) or with both CrMP and the nonselective antagonist of ET-1 receptors L-745142 (15 mg/kg iv).
Data analysis. Data are expressed as means ± SE. The concentration-response data derived from each vessel were fitted separately to a logistic function by nonlinear regression and the maximum asymptote of the curve (Rmax), and the concentration of ET-1 producing EC50 data was calculated with the use of commercially available software (Prism 2.01; GraphPad Software for Science; San Diego, CA). Data on vascular responsiveness to hypoxia and ET-1 in different groups of vessels were compared by ANOVA, followed by the Newman-Keuls post hoc analysis to make specific comparisons. Student's t-test was used to compare data on CO release and tissue ET-1 levels. The null hypothesis was rejected at P < 0.05.
HO expression and CO production in pulmonary arterial vessels. Proteins with the molecular mass of HO-1 and HO-2 were identified by immunoblotting in homogenates of pulmonary intralobar arteries (Fig. 1). The expression of HO-1 protein in pulmonary vessels was less intense (P < 0.05) in rats treated with HO-1 AS-ODN than in rats treated with HO-1 S-ODN (Fig. 1). The expression of HO-2 protein in vessels of rats treated with HO-2 AS-ODN was less intense (P < 0.05) than in vessels of rats treated with HO-2 S-ODN (Fig. 1).
Pulmonary intralobar arteries released CO into the head-space during incubation in Krebs buffer for 60 min (Fig. 2). CO release was virtually identical in vessels taken from rats treated with HO-1 S-ODN and HO-1 AS-ODN but was decreased (P < 0.05) in vessels from animals treated with HO-2 AS-ODN relative to the release from vessels of rats treated with HO-2 S-ODN. CO release from vessels bathed in media containing the HO inhibitor CrMP also was diminished (P < 0.05). CO release from vessels bathed in media gassed with 95% O2-5% CO2 (280 ± 44 pmol/l) was comparable to the release from vessels bathed in media gassed with 95% N2-5% CO2 (287 ± 70 pmol/l).
Effect of interventions that decrease HO expression and/or CO production on the pulmonary vascular response to acute hypoxia. KCl at 80 mmol/l produced comparable increase of isometric tension in rings of pulmonary intralobar artery taken from rats treated with HO-1 AS-ODN (1.17 ± 0.10 mN/mm; n = 8), HO-1 S-ODN (1.00 ± 0.08 mN/mm; n = 8), HO-2 AS-ODN (1.19 ± 0.11 mN/mm; n = 8), or HO-2 S-ODN (1.16 ± 0.07 mN/mm; n = 8). As shown in Fig. 3, basal isometric tension before hypoxia in segments of pulmonary intralobar artery taken from rats treated with HO-1 AS-ODN did not differ significantly from the values in vessels taken from rats treated with HO-1 S-ODN (0.18 ± 0.05 vs. 0.24 ± 0.04 mN/mm, P > 0.38). Basal isometric tension in vessels obtained from rats treated with HO-2 AS-ODN was generally increased (nonsignificant) relative to the basal tension values in vessels from rats treated with HO-2 S-ODN (0.30 ± 0.07 vs. 0.17 ± 0.03 mN/mm; P > 0.08). Pulmonary artery rings taken from rats treated with HO-2 AS-ODN developed isometric tension as a function of time during exposure to Krebs buffer gassed with 95% N2-5% CO2. The contractile response to hypoxia in vessels from rats treated with HO-1 AS-ODN was minimal when compared with that obtained in vessels from rats treated with HO-2 AS-ODN. Hypoxia did not promote development of isometric tension in vessels taken from rats treated with either HO-1 S-ODN or HO-2 S-ODN.
Figure 4 illustrates the effect of acute hypoxia on isometric tension development in endothelium-intact and -denuded pulmonary artery rings bathed in buffer with and without CrMP (15 μmol/l). KC1 at 80 mmol/l produced comparable increase of isometric tension in endothelium-intact and endothelium-denuded pulmonary intralobar artery rings (1.04 ± 0.06 vs. 1.06 ± 0.17 mN/mm). Basal isometric tension did not differ significantly among the groups before hypoxia. Hypoxia did not stimulate tension development in vessels not exposed to CrMP, regardless of whether the preparation was denuded of endothelium or not. In contrast, hypoxia promoted tension development in endothelium-intact preparations exposed to the HO inhibitor CrMP (15 μmol/l). Hypoxia also induced contraction of endothelium-denuded preparations after CrMP treatment, but the response was greatly attenuated (P < 0.05) relative to that in rings with endothelium. The inclusion of exogenous CO (1–100 μmol/l) into the bathing buffer caused concentration-dependent attenuation (P < 0.05) of the constrictor response to hypoxia in endothelium-intact vessels treated with CrMP (Fig. 5). In contrast, the inclusion of biliverdin (10 μmol/l) did not reduce hypoxia-induced pulmonary vascular contraction.
Pulmonary intralobar artery rings bathed in Krebs buffer containing PGF2α (1 μmol/l) developed isometric tension during hypoxia both in the absence (from 0.39 ± 0.19 to 1.09 ± 0.24 mN/mm; P < 0.05; n = 4) and the presence of CrMP (from 0.52 ± 0.16 to 2.43 ± 0.60 mN/mm; P < 0.05; n = 4). Hypoxia-induced vascular contraction in preparations pretreated with CrMP was more intense than in preparations not pretreated (1.91 ± 0.51 vs. 0.70 ± 0.19 mN/mm; P < 0.05); exogenous CO (1 μmol/l) attenuated (0.71 ± 0.15 mN/mm; P < 0.05, n = 4) hypoxia-induced vascular contraction in vessels pretreated with CrMP.
ET-1 and hypoxia-induced pulmonary vascular contraction. The tension development induced by acute hypoxia in rings of pulmonary intralobar arteries exposed to CrMP was greatly attenuated by the addition of the ET-1 receptor antagonist L-754142 (10 μmol/l) to the bathing buffer (Fig. 6).
Figure 7 illustrates the effect of ET-1 on tension development in rings of pulmonary intralobar arteries bathed in buffer not containing and containing the HO inhibitor CrMP (15 μmol/l), alone and with CO (1 μmol/l). ET-1 elicited concentration-dependent tension development in all the groups. Exposure of the vessels to CrMP caused a leftward shift in the concentration-response curve to the constrictor peptide, decreasing the EC50 but not the Rmax. The sensitization caused by ex vivo treatment with CrMP was offset by exogenous CO, which caused a rightward displacement of the concentration-response curve to ET-1 and increased the EC50 without altering the Rmax.
Figure 8 depicts data on ET-1 levels in pulmonary intralobar arteries incubated for 60 min in Krebs buffer gassed with 95% O2-5% CO2 or with 95% N2-5% CO2, both in the presence and absence of CrMP. ET-1 levels were comparable in vessels incubated during hypoxic and nonhypoxic conditions in the absence of CrMP. CrMP increased (P < 0.05) the vascular level of ET-1 both in nonhypoxic and hypoxic preparations. ET-1 levels were higher (P < 0.05) in hypoxic vessel treated with CrMP than in nonhypoxic preparations treated with the HO inhibitor. Also shown in Fig. 8, pulmonary intralobar arteries taken from rats treated with HO-2 S-ODN displayed similar levels of ET-1 when incubated under hypoxic and nonhypoxic conditions. In contrast, pulmonary vessels taken from rats treated with HO-2 AS-ODN displayed higher (P < 0.05) levels of ET-1 when incubated under hypoxic than nonhypoxic conditions. Relative to data in pulmonary arteries from rats treated with HO-2 S-ODN, pulmonary arteries from rats treated with HO-2 AS-ODN had higher (P < 0.05) levels of ET-1 both during incubation under nonhypoxic and hypoxic conditions.
Effect of interventions that inhibit HO and block ET-1 receptors on changes in pulmonary artery pressure produced by acute hypoxia. As illustrated in Fig. 9, pulmonary artery pressure increased (P < 0.05) acutely by 3.1 ± 0.1 mmHg in rats breathing a hypoxic gas mixture (5% O2-5% CO2-90% N2) over a 2-min period. Acute hypoxia elicited an even greater (P < 0.05) elevation of pulmonary arterial pressure after pretreatment of rats with CrMP (40 μmol/kg iv; 7.5 ± 0.7 mmHg). However, acute hypoxia did not increase pulmonary artery pressure in rats after pretreatment with both CrMP and the nonselective ET-1 receptor antagonist L745142 (15 mg/kg iv).
This study shows that rat pulmonary intralobar arteries express both HO-1 and HO-2 proteins, which is consistent with previous observations (17, 35) in pulmonary arteries of other animal species, and that the expression of HO-1 and HO-2 is depressed in vessels taken from rats treated with HO-1 AS-ODN and HO-2 AS-ODN, respectively. The study also demonstrates that rat pulmonary intralobar arteries incubated in Krebs buffer release CO into the headspace gas. CO release from these vessels is largely HO dependent because it was decreased to ∼30% of the control value by CrMP, a metalloporphyrin, which inhibits both HO-1 and HO-2 (29). That CO release from pulmonary intralobar arteries of rats treated with HO-2 AS-ODN, but not with HO-1 AS-ODN, is exceeded by that from vessels of animals treated with the corresponding scrambled antisense oligodeoxynucleotides implies that HO-2, rather than HO-1, is linked to CO release under the conditions of our study. HO-2-dependent formation of CO was documented previously in rat renal interlobar arteries and gracilis muscle arterioles (10, 37).
The major finding of our studies on isometric tension development, in isolated rat pulmonary intralobar arteries, is that acute hypoxia elicits contraction of vessels pretreated with CrMP to inhibit HO isoforms, and of vessels taken from rats pretreated with HO-2 AS-ODN to decrease HO-2 expression, but not of untreated vessels or of vessels obtained from rats pretreated with HO-2 S-ODN. Hypoxia also was found to elicit slight contraction of vessels taken from rats pretreated with HO-1 AS-ODN but not with HO-1 S-ODN. Previous reports (14) showed that mild precontraction of isolated rat pulmonary arteries with an agonist such as PGF2α enables these vessels to respond to acute hypoxia with a further contraction. In our study, before hypoxia, the basal isometric tension of untreated pulmonary vessels and of vessels taken from rats pretreated with HO-2 S-ODN tended to be exceeded (not significantly) by that of vessels pretreated with CrMP and vessels taken from rats pretreated with HO-2 AS-ODN. Conceivably, such borderline increments of basal tension may contribute to the enabling effect of pretreatment with CrMP or HO-2 AS-ODN on hypoxia-induced contraction of rat pulmonary arteries. However, this may not be the case because we found that pretreatment with CrMP intensifies hypoxia-induced contraction of pulmonary arterial vessels already precontracted with PGF2α. Our finding that interventions, which decrease the activity or the expression of HO isoforms, have an enabling or intensifying influence on hypoxia-induced contraction of rat pulmonary arteries that may be taken to indicate that one or more HO products interfere with the mechanism(s) underlying the effect of hypoxia on pulmonary vascular tone. A similar conclusion was inferred from observations that interventions that induce pulmonary HO-1 prevent the increase in pulmonary arterial pressure observed in rats exposed to normobaric hypoxia for 1 wk (4).
The second key finding of our study, in rat pulmonary intralobar arteries treated with CrMP, is that the contractile response to acute hypoxia is attenuated by the inclusion of exogenous CO but not of biliverdin into the bathing buffer. Exogenous CO also was reported to inhibit hypoxic vasoconstriction in an in situ, blood-perfused, lung preparation (26). Hence, CO is the product of pulmonary vascular HO activity most likely to interfere with the mechanism underlying hypoxia-induced contraction of pulmonary arterial vessels. Basal levels of CO production may be sufficient to disrupt such a mechanism because acute hypoxia did not increase CO release from pulmonary arterial vessels.
In agreement with some previous studies (14, 16, 38), we found that the contractile response to acute hypoxia is less intense in pulmonary intralobar arteries denuded of endothelium than in arteries with intact endothelium. Such an observation suggests participation of an endothelium-derived constrictor factor in the implementation of hypoxia-induced pulmonary vasoconstriction. Pulmonary vascular endothelial cells produce ET-1 (31), which elicits pulmonary vasoconstriction acting on ETA and ETB receptors (8). Participation of ET-1 in the pulmonary vasoconstrictor response to hypoxia is suggested by reports that pharmacological blockade of ET-1 receptors prevents hypoxia-induced pulmonary hypertension (23). However, reports (9, 16) that ET-1 antagonists inhibit contractile responses to hypoxia in isolated pulmonary arterial vessels conflict with reports that they do not (13). According to our study, in rat pulmonary intralobar arteries treated with CrMP, the ETA and ETB receptor blocker L-754142 attenuates the contractile response to hypoxia. Hence, during conditions of HO inhibition, hypoxia-induced contraction of pulmonary arterial vessels relies, at least in part, on a mechanism involving ET-1.
The third key finding of our study is that interventions that inhibit HO activity or HO-2 expression promote elevation of ET-1 levels in pulmonary intralobar arteries. Moreover, we also found that HO inhibition sensitizes the vascular smooth muscle to the contracting action of ET-1. That treatment with HO-2 AS-ODN or with CrMP increases ET-1 levels in pulmonary arterial vessels, particularly during hypoxic conditions, is in line with a report (18) that inhibition of HO augments the production of ET-1 by human umbilical vein endothelial cells cocultured with vascular smooth muscle cells during hypoxic conditions. These observations suggest that a product of HO activity, presumably CO, inhibits endothelial cell synthesis of ET-1, an action that may counteract the stimulatory action of hypoxia on ET-1 production (11). That CrMP sensitizes pulmonary intralobar arteries to ET-1-induced contraction is attributable to reduction of vascular CO because the sensitizing effect could be offset by exogenous CO. Altogether, these observations suggest that CO manufactured by pulmonary arterial vessels is an inhibitory modulator of both the vascular formation and constrictor action of ET-1.
Previous studies (10, 30, 37) documented that endogenous CO reduces the sensitivity of systemic small arterial vessels to constrictor stimuli, an action that was attributed to activation of large conductance KCa channels in vascular smooth muscle. On the other hand, in the pulmonary circulation of rats, activation of soluble guanylyl cyclase rather than of KCa channels is involved in the vasodilatory effect of exogenous CO (21). Whether or not the inhibitory influence of HO-derived CO on the responsiveness of pulmonary intralobar arteries to ET-1 involves activation of K+ channels is unknown. The possibility merits consideration in view of observations linking hypoxia-induced contraction of pulmonary vascular smooth muscle cells to a reduction in K+ currents, which may involve synergistic interactions with ET-1 (16, 25, 34).
The regulatory influence of HO-derived CO on hypoxia-induced pulmonary vasoconstriction is not limited to isolated vascular preparations. In this regard, our study in anesthetized rats documented that the elevation of pulmonary artery pressure caused by breathing a hypoxic gas mixture was intensified by pretreatment with CrMP to inhibit HO. That concurrent pretreatment with the ET-1 receptor antagonist L-745142 blunts the pulmonary pressor response to acute hypoxia in such animals suggests that endogenous CO minimizes the in vivo activity of an ET-1-dependent pulmonary pressor mechanism induced by acute hypoxic conditions.
In summary, this study demonstrates that pulmonary arterial vessels express HO-1 and HO-2 and manufacture CO. HO-derived CO interferes with the expression of hypoxia-induced pulmonary vasoconstriction both ex vivo and in vivo, in part by reducing vascular ET-1 levels and the sensitivity of the smooth muscle to the contracting action of the peptide. Hence, a heme-HO system intrinsic to the pulmonary vasculature modulates the constrictor response of pulmonary arterial vessels to acute hypoxia.
We thank Jennifer Brown for assistance with this study.
This work was supported by American Heart Association (New York Affiliate) Grant 9930291T, by American Lung Association Grant RG-058-N, and by National Institutes of Health Grants HL-18579, HL-34300, and DK-56601.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2004 by the American Physiological Society


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"St. Petersburg is one of the..." Metro Tip by travelmad478
Metro, Saint Petersburg: 84 reviews and 92 photos
St. Petersburg is one of the most accessible cities in Russia. You can fly there from elsewhere in Russia, or from Europe. If you're coming from Moscow, the best way is to take the overnight train. This takes between six and eight hours and is a definite must-do experience. There is a daytime train as well, but the views along the way aren't much to look at, so you may as well use the time for sleeping and have more days to spend in St. Petersburg!
St. Petersburg has a metro system similar to Moscow's in style and utility. One interesting feature is that its trains run VERY far underground, because of the canals. The escalators are a little terrifying--very fast, very long, and if you don't keep your eyes on your shoes you can get a real case of vertigo! Above ground, there are the canals, but these are not really used for public transportation. The Venice of the North it may be, but there are no gondolas in St. Petersburg. Take a taxi instead.
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CheapOAir.com: LA Food Guide
CheapOair has a new article in their Local Guides up entitled "Los Angeles Food Guide: Daybreak to Dinner," and we're thrilled that it includes a mention of Langer's Delicatessen-Restaurant. We're among some terrific and innovative company; how many of their recommendations have you tried? Thank you, CheapOair!
Langer's Makes Fall 2016 Eater 38 Essential Restaurants
All of us at Langer's Delicatessen-Restaurant are honored to be named to Eater's "38 Essential Los Angeles Restaurants" for Fall 2016. This is an elite list encompassing a wide range of cuisines and dining formats, and to be included is extremely meaningful to us. Thank you, Matthew Kang and Eater!
LAPD Chief Charlie Beck and CBS2's Pat Harvey at Langer's Deli
LAPD Chief Beck sits down with CBS2's Pat Harvey at Langer's Delicatessen to discuss current policing strategies. Above is the full-length interview.
This is a shorter version that aired earlier.
7th Annual Rampart Golf Tournament
Help Langer's Delicatessen support the Los Angeles Police Department's Rampart Division – home to the officers who patrol our area of LA – by signing up your foursome now to participate in the 7th Annual Rampart Golf Tournament. Put on by the Rampart Boosters, this tournament will be held Friday, October 14, 2016, at Montebello Golf Course. A portion of the tournament profits will be donated to the USC Norris Comprehensive Cancer Center (2015's contribution totalled $2500).
Click here to download the sign-up form.
Click here to read the complete letter from Commanding Officer Jeff Nolte now.
Please do what you can to support this worthy cause. All of us at Langer's Delicatessen appreciate your support and participation.
Silver Lake Blog: Still Going Strong
We're thrilled with the great new article published on the Silver Lake Blog about Langer's Delicatessen. Here's an excerpt:
Langer's menu is as long as it is classic, with traditional Jewish deli nosh, matzo ball soup, brisket, corned and roast beef, and homemade desserts. The item to behold is the #19. Let's dissect, shall we? Untoasted rye, Russian dressing, creamy coleslaw, and a couple slices of Swiss—all in service of the hand-sliced, juicy, smoky, beefy pastrami. On the side: a single dill pickle.
Norm Langer on "Weekend Warrior" with Dr. Robert Klapper
Here's something really fun: Norm Langer joined Dr. Robert Klapper on his ESPN LA 710 radio show "Weekend Warrior" recently, and they had a great discussion. Click the link to give it a listen!
Bon Appetit: Plan Your Ultimate LA Restaurant Weekend
Here's an absolutely fantastic video by Sheena Rao of Bon Appetit Magazine entitled "Plan Your Ultimate LA Restaurant Weekend." It includes a visit to Langer's Delicatessen, and it's a total must-watch! Thank you, Sheena and Bon Appetit, for including us!
Eater: 35 Classic Restaurants Every Angeleno Must Try
Matthew Kang and Farley Elliott have done it again with their latest Eater.com list, "35 Classic Restaurants Every Angeleno Must Try." It's packed with so many classics, you'll want to visit each one. We are honored to be included in this list. Which are your favorites?
Click here to read the complete list. Thank you, Matthew and Farley! – The Langers
MyJewishLearning.com: The 9 Best Places for Jewish Food in LA
Great new article by Shannon Sarna at MyJewishLearning.com on "The 9 Best Places for Jewish Food in LA." We're thrilled to be included on the list. How many of these fine establishments have you tried?
VoyageLA.com: The Non-Snobby LA Dining Guide
Here's a great new article from our friends at VoyageLA.com entitled "The Non-Snobby LA Dining Guide" – and it's just that – their favorite places that serve "really, really good food." We're thrilled to be included, thank you! How many of their other selections have you visited? It's a neat and diverse list!
Pastronomy Tour with Adam Gertler
Thanks to Adam Gertler and everyone who attended the "Pastronomy" tour a week ago, which included #19s from Langer's Delicatessen. We thank you all!
They Eat: Langer's Deli Video Visit
The ladies of They Eat visited Langer's Delicatessen recently and tried our #19 based on the recommendation of Jonathan Gold of the Los Angeles Times. Their verdict?


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The Manual of Minor Oral Surgery for the General Dentist, Second Edition continues the aim of providing clear and practical guidance to common surgical procedures encountered in general practice. Fully revised and updated with three additional chapters, the book approaches each procedure through detailed, step-by-step description and illustration. Ideal for general dental practitioners and students, the book is an indispensible tool for planning, performing, and evaluating a range of surgical procedures in day-to-day practice. The Manual of Minor Oral Surgery for the General Dentist begins with an expanded chapter on patient evaluation and history taking and a new chapter on managing the patient with medical comorbidities. It also address infections and sedation besides procedural chapters on such topics as third molar extractions, preprosthetic surgery, surgical implantology, crown-lengthening, and biopsy of oral lesions.The advantages of autografts are that they have no possibility of disease transmission and contain osteoinductive properties. The disadvantage is that it requires that the patient has a donor site, which carries a potential for additional morbidity.
|Manual of Minor Oral Surgery for the General Dentist
|Pushkar Mehra, Richard D'Innocenzo
|John Wiley & Sons - 2015-05-15


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Motorized bikes in Hollywood movies or other films?
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Motorized bikes in Hollywood movies or other films?
I once saw a foreign film and maybe a old B&W with a whizzer in it. Have any of you noted films with these moving modern marvels in them? I thought this to be a good question for your hot laptop picnic date on that bike trail in the middle of nowhere with just a tent exhaustion from whatever and nothing to do but attept at being romantic on your bicycle date adventure while it rains outside. If you do not know of one film one or just download 1000 youtube flix and play the best ones. I just found an old chainsaw with a 34cc mCcullough I think? It has a bad pull start and that is it I THINK.. I shall see soon enough..
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factory supply high purity Mesterolone / Mesterolon CAS: 1424-00-6
factory supply high purity Mesterolone / Mesterolon CAS: 1424-00-6
Synonyms: 17-beta-hydroxy-1-alpha-methyl-5-alpha-androstan-3-on;17-hydroxy-1-methyl-,(1-alpha,5-alpha,17-beta)-androstan-3-on;1-alpha-methyl-17-beta-hydroxy-5-alpha-androstan-3-one;1-alpha-methyl-5-alpha-androstan-17-beta-ol-3-one;androviron;mesteranum;mesterolon;mesterolone--deascheduleiii
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Adoption Donation $ 450
Located: in New England
Age: 2 years
Weight: 9 lbs
Roxie is a sweet little chihuahua mix with very long legs (perhaps some Italian greyhound?). She was an owner release rescued from a TX shelter by one of our Louisiana Rescue partners. Roxie was very pregnant and soon welcomed 5 puppies who have since been weaned. She is now ready for a home of her own. She is estimated to be around 2 years old and weighs 9 lbs. She is heartworm negative, UTD on immunizations, and spayed.
Roxie loves her people and bonds quickly to her person/family. She is however very nervous and perhaps a little fearful about meeting new people because she gets so attached. She will need a patient adopter that understands she will need a few days to adjust before she will make you her "special person". Once she feels comfortable she is very playful and enjoys playing with other small dogs. She is good with cats too. She loves to run with those tiny long legs and would do best with a fenced in yard.
She is housetrained/pee pad trained. Although she will go outside she doesn't like to get her feet wet and prefers to use a pee pad inside. She is crated trained and has been sleeping in one at night. She is a great little dog that will make someone a wonderful companion!
If you are interested in adopting me, please fill out an application on our website www.fohari.org and email for more information: email@example.com
Please check out our website for how to Adopt, Adoptions events, Fostering and more!
Normally we do not process applications unless a specific dog is selected, along with submitting a deposit of $200 using our Paypal Donate link. Please understand we are all volunteers with limited resources - your deposit tells us you are serious.
Once we have your deposit we will hold the dog for you while we process your application. If you are not approved to adopt or we can not provide the dog you are interested in, your deposit is refunded. If you are approved, the deposit is applied toward the total donation of the dog.
If the dog is not a good match, we will work with you to find another dog, but the deposit is NOT refundable. We want you to be certain that this is a decision your have thought through thoroughly & not just a whim so if YOU change your mind for ANY reason , your deposit is NOT REFUNDABLE !
If you would like to HELP any of our special rescued dogs by making a donation or
If you would like to place a DEPOSIT for a dog while we process your application, you can use this secure & safe site on Paypal - please click on symbol below:
Transport costs are normally included in the donation unless otherwise noted.
If you wish to call us, please call between the hours of 10 AM and 7PM at 401-234-4499.
If you leave a message, a volunteer will return your call ASAP.
If you would rather email us, please email: firstname.lastname@example.com
Enter the dogs name in the subject line. Thank you!
FRIENDS of HOMELESS ANIMALS, INC. is a RHODE ISLAND NON PROFIT 501 (C)(3) RESCUE
Please remember that we are ALL volunteers & will respond to you as quickly as we can in all communications. We are not paid volunteers and try to keep the phones and emails manned but sometimes there may be a lapse in time. We appreciate your patience.
Step 1 - Complete an online application - http://fohari.org/aa
Step 2 - Please reserve your dog by making a $200 deposit on Paypal - https://www.paypal.com
E-mail address to use for deposit (which is applied toward total donation) is: firstname.lastname@example.com
You can meet any of our local dogs with JUST an online application and NO deposit, but must be approved, etc. 1st in order to take your dog home.
Step 3 - Let your references know that a volunteer will be contacting them.
Step 4 - Once your references are contacted, a volunteer will be in touch to arrange your home visit.
Step 5 - Once you have been approved, pick up information, balance due, and adoption contract will be e-mailed to you.
Please remember our dogs generally all have a pull fee from a shelter, LOTS of vet costs for initial shots and tests, spay or neuter, and then transport costs to bring the dogs to our area. This is just the beginning of the costs for a rescue. We then depend on our volunteers to buy the dog food, we pay for any additional vetting costs and grooming for the dog. There are many costs and we depend on our adoption donations to HELP pay our costs. We are a non-profit charity 501(c)3 and depend on donations for rescuing our dogs. Most times, the adoption fee does not cover the costs associated with that dogs rescue costs.
Thank You!
Your message has been sent to Friends of Homeless Animals, Inc.(FOHA).
You'll receive a copy, too, at to help you keep track of which pets you've inquired about, and which shelters and rescues you've emailed.
NOTE: Some shelters have physical locations you can visit; some of these shelters may only have pets for a limited time, so please do not wait for a reply—just go visit the shelter! Other organizations are rescue groups run by busy volunteers who may take a while to reply. You can find information about the shelter or rescue group caring for this pet, and their adoption procedures, on the pet's details page on Adopt-a-Pet.com.


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Wrapping up its session in Paris that began several weeks ago, yesterday the United Nation's cultural agency adopted a Palestinian and Arab state-sponsored resolution on Jerusalem that ignores both Jewish and Christian attachments to Jerusalem's sacred sites.
UNESCO's Exec Board ratifies resolution purging Jewish connection to Temple Mount
Climate Alarmists Target New "Greenhouse Gas" in Latest Deal
Now that the Paris Climate accords targeting carbon dioxide are being implemented, with regulatory restrictions and wealth redistribution systems being firmly established, climate alarmists need a new target.
UNESCO attempts to erase Jewish connection to Temple Mount
The United Nation's cultural body—UNESCO (United Nations Educational, Scientific and Cultural Organization)—passed a resolution in Paris yesterday that challenges both Jewish and Christian ties to Jerusalem's holy sites.
The resolution was passed as Item 25 (titled "Occupied Palestine") of the provisional agenda for UNESCO Executive Board's 200th session.
The document (full text here) was...
Airline industry hijacked by UN climate accord
President Obama recently touted the "Paris Agreement" as a "turning point" in his misguided attempt to save the planet from climate change.
However, the rules, regulations, and fiscal schemes associated with the implementation mean that airlines are being hijacked into making the "first international aviation climate deal."
In a nutshell, airlines will pay a...
UN: The U. S. Should Pay Reparations to Black People for Slavery
Remember that UN working group who suggested that today's police shootings are reminiscent of lynchings? Well, they also recommend that the U. S. pay reparations to black people for slavery.
The Christian Science Monitor reports:
"Past injustices and crimes against African Americans need to be addressed with reparatory justice," the report said. The...
UN: Police Shootings of Black People Reminiscent of Lynchings
Police killings of black people in the United States are reminiscent of lynchings and the government must do far more to protect them, a United Nations working group says in a report that will be debated at the U.N. Human Rights Council on Monday.
The hard-hitting criticism – drawing a...
Netanyahu at UN: Invites Abbas to Knesset, willing to go to Ramallah
Benjamin Netanyahu spoke at the U.N. today.
As usual, it was an excellent speech.
The headline is that Netanyahu offered to have Palestinian President speak at the Israeli Knesset (parliament) and for Netanhahu to speak at the parliament in Ramallah.
President Abbas, I invite you to come...
'This Is Not the Faculty Lounge': Foreign Relations Head Rips Obama UN Speech
Richard Haass is the quintessential member of the foreign policy establishment. Long-time President of the Council on Foreign Relations, Haass has served in Republican and Democrat administrations and advised candidates from both parties. In this election, he has been very critical of Donald Trump.
So no taint of partisanship can be applied...
Report Finds UN Ignores, Denies Corruption
The UN's Joint Inspection Unit (JIU) has found during their nine month investigation that the organization simply ignores corruption when it comes to light.
The investigators found that UN officials remain in a "st...
Family of 13-year-old girl murdered by Palestinian terrorist ascends Temple Mount
On Tuesday morning July 12, 2016, the family of Hallel Yaffa Ariel, the 13-year-old Israeli girl who was brutally stabbed to death on June 30th as she lay asleep in her bed, was granted special permission to visit the Temple Mount in Jerusalem—the most sacred site in Judaism.
Hallel's anguished parents, Rina...
VIDEO – How UN Refugee agency teaches children to hate and attack Jews
We recently showed a video about how Palestinian incitement to violence is generated both top-down from the Palestinian Authority, and bottom-up through social media, VIDEO: No truly "Lone Wolves" in the Palestinian Knife Intifada
A newly released video expands on the problem of...
Obama drains $500M From Zika response to U.N. Climate Fund
In February, President Obama said we should not "panic over Zika."
At the same time, he asked Congress for $1.8 billion in funding for the resources to combat the Zika virus, the pathogen spreading rapidly through the Americas that can cause birth defects and neurological problems. In a rare display of fiscal...
UN Child Sex Abuse Whistleblower Resigns
Anders Kompass, who worked as director of field operations at the UN human rights office, has resigned after the organization did not hold senior officials accountable for human rights abuses.
The UN suspended Kompass after he leaked a report that said French troops sexually abused children in the Central African Republic.
However, the...
Saudi Arabia Blackmails UN Over Children's Rights Abuse List
The United Nations has shown they care more about money than children's rights as they removed Saudi Arabia from a list of countries who committed atrocities in Yemen.
The kingdom threatened to pull money from numerous UN programs if they remained on the list. UN General Secretary Ban Ki-moon immediately gave into...
Muslim Countries Block LGBT Groups from U.N. AIDS Meeting
While Americans squabble over which bathroom stall to use, a block of fifty-one Muslim countries blocked eleven gay and transgendered groups from attending an upcoming AIDS meeting at the United Nations, scheduled for June.
Western countries are not happy.
White House Looking for "Under the Radar" Routes for Syrian Refugees
Apparently, the White House is bowing to pressure from the Office of the United Nations High Commissioner for Refugees (yes, such a position actually exists) and is going to look for alternate ways to bring Syrian refugees into the country.
The Obama administration appears to be bowing to international pressure...
1975 – When Vassar students protested anti-Semitism masquerading as anti-Zionism
The Vassar College Student Association council is voting anonymously on March 6, 2016, on an anti-Israel Boycott, Divestment and Sanctions resolution proposed by Vassar Students for Justice in Palestine (SJP) and Vassar Jewish Voice for Peace (JVP). For details, see Vassar anti-Israel activists attempt stealth academic boycott Resolution.
For years the BDS campaign on campus...


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Farseer with Eldritch Storm, Mind War, and Rune of Witnessing
3 Warlocks with Enhance, Destructor x2, and Singing Spear
208 points
Idea is to Mind War the HQ to take it out a little bit easier without engaging. Eldritch Storm a troop, and follow up with Scatter lases and range fire, and assault if possible the same turn since the target can't save wounds.
155 points
Face it. In a 500 point match, this will be hard to handle.
5 Dire Avengers
With Exarch with 2 Shuriken Catapults and Bladestorm
92 points
10 Guardians
With Scatter Laser (add Warlock with Avatar)
95 points (120 points)
Wave Serpent (dedicated transport)
With twin-linked scatter lasers (I'd add Star Engine and Spirit stones if using Avatar)
115 points (140 points)
Total 510 points (507 points)
Of course, this is just the Battle Set with the Farseer and 3 Warlocks box or the Avatar added. Just shows what you can do with a basic set up.
I plan to add the following for a 1000 point build depending if enemy is more vehicle or infantry heavy though I could probably just halve my model count in both units to incorporate both:
Jain Zar
190 points
10 Howling Banshees
With Exarch with Mirror Swords
182 points
205 points
10 Fire Dragons
With Exarch with Dragon's Breath Flamer
192 points
3 War Walkers
With Shurkien Cannons and Spirit stones
120 points
492 points (525 points)
Iunno. I see this as being my first 1000 point army to expand on. I definitely plan to get both those Elite units as I move up to the 1500 point army. And a Harlequin Troupe with Shadowseer and Death Jester.
I eventually plan on buying 1 of EVERY Eldar model to complete the minimum requirements for a unit for multiple builds. I like to be versatile, and learn new things as i go instead all at once.
I don't know how many Il-Kaithe armies exist, but that's gonna be my color scheme. My two favorite colrs. Purple and green. w00t! =D
A small council on foot is not a very useful unit. Mindwar and eldrich storm are two of the worst powers in general a farseer can take. Doom, fortune, and guide can multiply the effect of an eldar unit/army making them more powerful over all. Not saying they are bad powers but I recommend the others in most cases. Avatar is a good HQ at the points level. the 1k lists both have two general problems 1, they have an aspect unit that works best in a transport and no transport for them. 2, both have a phoenix lord. These underperform for their cost when compared to standard HQs or Eldrad, Yriel. Perhaps take the avatar list at 500 then instead of the Phoenix lord grab a simple farseer and a transport for the elite unit you decide on for the 1000 point list. Oh and don't take spiritstones on the walkers they are redundant in a squad.
dude dont take death jesters they are terrible... i know they look cool but thats as far as they get. here are the reasons
1) you cant fire the jester and still fleet which on a combat squad is very important.
2) death jesters do not have the option of taking a kiss drasticaly reduceing their combat effectivness.
3) its 10 points for a cool sounding shurken cannon, leave shooting power to other squads like dire avengers or reapers they are much better at it.
also i play the avatar frequently in larger point battles as well as smaller ones however beastly he is too expensive for 500 point battles. take a farseer with doom and increase the number of dire avengers you have.
hope my advice helps good luck!!!
I am having trouble following what is going on with this thread.
But in generaly, avatars at 500 pts are beastly and wheni played a 500pt tournament the guy got 2nd place, beat by me in first place cause i ran away from him all game.
Dont take P,Lords. No no no.
No death jesters.
no dire avengers, banshees, fire dragons, or storm guardians without wave serpeants.
No eldritch storm or mind war. Doom +guide+fortune=yes
Eldar -APOC- 6500 Points
Chaos Daemons -Fate Crusher- 3500 Points
Grey knights - 1000 Points
Well, with my list, I don't plan on them being competitive at all. I think this idea was assumed by those who read it. With me being new, I plan on trying different tactics to hone my skills. As well as, my friend is using Chaos and plans on using his Abaddon, so with me using a Phoenix Lord, I plan on having those "epic battles" with him. Which is why I usually include a IC. Also, I'm the type of person who tries to make "unpopular" units work. I'm not a huge fan of playing and only relying on what everyone else does. I'm more of a risk taker than play by the book person.
Though I do plan on making a competitive list that is not as heavily mechanized as I've seen.
Thanks to all who have replied.
Hello and welcome to the Eldar side of the coin. Death to the Mon-Keigh!
I was once as you are, I foolishly picked Biel-Tan as my first army to paint and collect, which in hindsight was a big mistake. Painting them is still a pain, but at least you will avoid that aspect.
The second problem is having a whole bunch of aspect warriors. This is quite pricey for starters, especially since you pretty much need a full squad for them to be at their best (Not all, but most).
I think that your plan of collecting and trying new things is great. But I also think that you will quickly get bored with losing, and with only collecting minimal squads of things you will never see them live up to their potential. I'd suggest at least starting with a traditional-ish list to have a good base to expand upon, this will give you a decent chance of winning.
So for your first 500 point list I suggest something like the following:
1 Doomseer
10 Dire Avengers + Bladestorm + Wave Serpent
5 Rangers
1 Fire Prism
It's slightly over 500 points, but you can always drop an Avengers or two if your opponent is stingy.
Then for future builds you can expand with any aspect warriors you are interested in, and you have a solid base that will help you win. Another nice thing is that this gives you a Serpent for use with the Aspect Warriors that really need one, although your Avengers will be gimped by this but they are still playable (and it's not very common to see Avengers without transports if you want to try that).
Units that really need the Serpent are Banshees, Avengers and Fire Dragons. But you can transport Fire Dragons in a Falcon if you wish since 5 are usually more than enough.
I'd avoid the epic battles with your opponent using Phoenix Lords (they pretty much suck), if you have some pimped out Banshee Exarch fighting him it will still look pretty cool.
If you still want to try the Phoenix Lords I'd suggest only getting Jain Zar and Karandras, these are the only two that might be worth their points in some cases. Eldrad is also pretty nice for higher point games.
Anyway, let us know what you decide to go with and how it goes. It's always nice to see new things, and I hope you enjoy playing the Eldar.
Yeah, I plan on collecting full squads and such as I go along. Trying not to get everything at once because I would be just overwhelmed with everything that I could do. Just as you said, going for key ones that will be VERY handy in most situations like the Banshees and Dragons.
I still plan on getting and using those Phoenix Lords. Just for as I said, those friendly epic battles that my friend and I stage. So he isn't the only with a point sink out on the table. Also like the idea of the recreation battle between Abbadon vs Eldrad and Maugen Ra =P
Definitely plan on getting more Guardians and Dire Avengers. And some Rangers to try out different troop selections. Is there much difference between Storm and regular Guardians miniature wise? They look the same save for them having pony tails. I figure I could just glue a twisty-tie (first thing I thought of) to the back of their helmets or something. Or do they have specific weapons that set them apart?
Also, I like the grenade bombings the Swooping Hawks can do. Are they able to bomb then Skyleap after wards in the same turn, or must they wait til next turn to Skyleap? And how practical would you say it is using that ability a few times in match?
Last question (for now), when assaulting with Banshees, would they get a total of 3 attacks each? +1 for assaulting, +1 for having 2 weapons (pistol and sword), and their base 1A?


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how do you release the top?
2 Answers
There are four torx bolts that need to be loosened with a torx wrench that should be in the center console. Two of the bolts are in the front, under the sun visors. The other two are in the back of the roof panel going into the B-pillar. Check the Corvette Action Center for more info: http://www.corvetteactioncenter.com/forums/1984-1996-corvettes/
1 out of 1 people think this is helpful.
Just make sure you are not going 130 down the freeway when you loosen the bolts. Get yourself an owner's manual off eBay if you get a chance and you might find all sorts of good info on the car.
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True red mazda for sale on US's largest classifieds sites (89 results)
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Used 2007 Mazda MAZDA3 For Sale
This Mazda 3 is the Sport model and has extras including: Auxiliary input, cd player, tilt wheel, cruise control, all power, keyless entry, rear spoiler, alloy wheels and more! This vehicle has a NADA Value of $6,175 and a Kelly Blue Book Value of $6,742, we have it priced to sell at $4,995! This mean...
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2013 Mazda MX-5 Miata Sport
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The new home of
3 reviews
This detached holiday villa, set in a peaceful area and enjoying a private swimming pool, is within walking distance of the local shops and only 2km from the town of Clermont l'Hérault, which offers all facilities. The seaside resort of Cap d'Agde, 50km, is one of the finest on the Mediterranean coastline. Discover the local medieval villages, grottes and market towns, and the art and crafts village of Pénzenas, 20km. Lake Salagou, in a stunning setting, with water sports provides useful entertainment, as does the lively sporting resort of Lamalou-les-Bains, with a golf course, 36km. Béziers, 45km, and the sun drenched capital of Languedoc Roussillon and Montpellier, 50km, both provide cultural delights. Walkers will marvel in the beauty of the Haut Languedoc Regional Nature Park. An all year round holiday destination to suit all. When returning to the property to enjoy an al-fresco meal under the stars with a bottle of local wine.
All on ground floor: Living/dining room/kitchen with patio doors to terrace. Two bedrooms: One double with en-suite shower room/WC, one twin. Shower room (no WC). Separate WC
Location: Nébian 500m (shops), Clermont 2km (all facilities), Lake Salagou 9km, Béziers 45km (all facilities), Cap d'Agde 50km (beaches), Montpellier 50km.
0 reviews
Located near Narbonne and bordered by the Canal de la Robine, these semi-detached holiday homes will assure you of a warm welcome. They are set in a traditional vineyard of 4 hectares in the heart of the Regional National Park of Narbonne and where the owner also lives on site. Relax on the terrace in the shade of plane trees, where you can admire the cathedral of Narbonne, the Massif of Clape and the Pyrenees. An outdoor play area is available, and a shared courtyard is an ideal place to meet for an evening barbecue with your neighbours. Guests at both properties also enjoy shared use of the Jacuzzi and sauna. The Fontfroide Abbey is worth a visit and the beaches of Gruissan await you. Carcassonne is 60km, and the airport, 70km. Shop and restaurant 3km, beach 17km.Located near Narbonne and bordered by the Canal de la Robine, these semi-detached holiday homes will assure you of a warm welcome. They are set in a traditional vineyard of 4 hectares in the heart of the Regional National Park of Narbonne and where the owner also lives on site. Relax on the terrace in the shade of plane trees, where you can admire the cathedral of Narbonne, the Massif of Clape and the Pyrenees. An outdoor play area is available, and a shared courtyard is an ideal place to meet for an evening barbecue with your neighbours.
Guests at both properties also enjoy shared use of the Jacuzzi and sauna.
The Fontfroide Abbey is worth a visit and the beaches of Gruissan await you. Carcassonne is 60km, and the airport, 70km.
Shop and restaurant 3km, beach 17km.
Ground floor: Lounge/kitchen/diner, shower room with basin (no toilet), separate toilet. First floor: Separate toilet (no basin), 2 double bedrooms.
Electric heating, cot, colour TV (French channels only), wi-fi, washing machine, dishwasher, microwave, terrace, shared outdoor furniture, shared barbecue, off road parking for 3 cars. One pet welcome. NB: Steep, open tread, turning stairs to first floor.
This 3rd floor holiday apartment with a large bay window and spacious covered balcony has lovely views of the mountains and the village of Vernet-les-Bains. The apartment is ideally situated for lovely walks in the mountains and fishing in the nearby river. The town of Prades (19 km) hosts the annual music festival dedicated to the cellist, Pablo Casals (month of August). The Font-Romeu ski resort is only 48km away. The "Train Jaune" tourist train from Villefranche-de-Conflent, a stronghold of the past steeped in history, will take you to Font-Romeu through breathtaking landscapes. The city of Perpignan with a prestigious past, the capital of French Catalonia, is 50km away and Spain is 3 hours drive. Shop and restaurant 200m.
All on third floor: Lounge/diner, kitchen, bathroom with toilet and basin, 1 double bedroom, double sofa bed in lounge.
Electric heating, DVD player, washing machine, microwave, balcony, outdoor furniture, off road parking for 1 car. One pet welcome. No smoking please.
1 reviews
This detached holiday villla, totally independent from the owner's home, lies peacefully on the edge of a small village between Clermont-l'Herault and Pézenas. Well equipped with delightful modern décor, and French windows opening onto the garden, it has a private raised swimming pool (5.5m x 3m; depth 1.35m) and 7-person Jacuzzi. This excellent central touring base is within a short drive of the Mediterranean's golden sandy beaches, 35km. Discover the arts and crafts town of Pézenas, very proud of its past and with many interesting streets and mansions - unchanged since the 17th century. Visit the sun drenched historical capital of Languedoc, Montpellier, the wine capital of Beziers or the authentic fishing village of Sète. Shop and café/bar 0.5km, restaurant 2km, beach 35km.
All on ground floor: Lounge/kitchen/diner, shower room with basin, separate toilet, 1 double bedroom, double sofa bed in lounge.
Electric central heating, cot, highchair, colour TV (French channels only), DVD player, CD player, wi-fi, washing machine, dishwasher, freezer, microwave, private enclosed garden, terrace, garden furniture, barbecue, private jacuzzi for 7, off road parking for 2 cars. One pet welcome.
This delightful, modern holiday village is located between the sun-drenched historical towns of Nîmes and Montpellier, close to La Camargue and only 22km from the endless miles of golden sandy beaches of the Mediterranean. These semi-detached holiday properties (F30150, F30151 and F30152) are situated in the holiday village, and enjoy use of a large outdoor swimming pool, a water amusement area for children, a toddlers' pool and also an indoor heated pool which is open all year. There is a spa and relaxation area (at extra cost), tennis court, a children's play area, a multi-sport pitch, a laundry and a small grocery shop. Joined to the holiday village is a 3 star hotel with bar and restaurant. Jasse de Camargue is an excellent touring base, with interesting and varied excursion possibilities to be enjoyed only a short drive away. The Camargue, the most original and romantic region of Provence, has largely been preserved in its natural state through its designation, in 1927, as a botanical and zoological nature reserve. Wildlife abounds, the sun shines and there are the famous pilgrimages to Saintes-Maries-de-la-Mer. A trip north takes you into the Cevennes Regional Nature Park, a haven for nature lovers and walking enthusiasts.
Ground floor: Living/dining room with French doors to terrace, and corner kitchen. Bathroom with over-bath shower. Separate WC. First floor: Two bedrooms: One double, one twin. Tiled floors throughout.
Location: 200m from shops, bar, restaurant, 20km from Montpellier (Place de la Comédie, Jardin-des-Plantes de Montpellier and châteaux), 20km from Nîmes (shops, galleries, airport), 20km from Aigues Mortes, 40km from Arles.
All properties: Private garden with step
5 reviews
A beautifully renovated old bergerie, in lovely setting amongst vineyards and orchards. There are delightful south-facing views from house, terraces and superb pool surrounded by hedge and stone walls. The garden has olive trees and lavender bushes with sunny and shaded terraces for al-fresco dining, and along with the pool is totally private. The house is attached to the discreet English owners' property and the pool is cleaned every morning before 8am. The property is decorated and furnished in Provençal colours with original artwork, tiled floors and great attention to detail. Take walks in the aromatic heathland all around the house and breathe in the scent of wild thyme, lavender and mint. Saint-Laurent-la-Vernède, with its 15th century fort and award winning wine Cave, is a 4 minute drive and has a bakery and grocery store.
Ground floor: Living/dining room with French windows to terrace. Kitchen. Open-sided stairs to first floor: Double bedroom with en-suite bathroom with shower cubicle and WC. Twin bedroom. Bathroom with shower cubicle. Separate WC. All first floor rooms with beams
Location: 10km from Lussan (medieval walled village, restaurants, shops), 15km from Uzès (shops, cafés, restaurants, markets), 50km from Orange (Roman theatre, Arc de Triomphe), 60km from Avignon (historic city, all facilities), 60km from Nîmes (Roman ruins, shops, bars, nightlife).
One of three villas comfortably converted and set on a working vineyard, Villa Apiteo is located on a vineyard with views over the Corbières vines. Enjoy the shared fenced swimming pool with kitchenette and shower room. Wine tasting is available on site in the owners' cave but it's worth exploring further afield as well. The area is famous for its wine production and much of the landscape is dominated by vineyards and the Corbières hills. The village of Ferrals-les-Corbières, with restaurant and shops, is within walking distance. More shops can be found in Lézignan 6km away. Don't miss a day in Carcassonne, 38km, with its narrow streets and fabulous pavement cafés. The Canal-du-Midi is also just 10km away and is ideal for walks and cycling along its tree-lined tow path.
Ground floor: Living room. Dining room. Kitchen. Kingsize bedroom. Twin bedroom. Shower room (no WC). Separate WC. Open-tread stairs to mezzanine: Sitting room with single sofa bed
Location: 6km from Lézignan-Corbières (shops), 38km from Carcassonne (UNESCO World Heritage Site, all facilities).
Situated on the first floor of a charming townhouse (the owners live on the ground floor), this lovely, air conditioned holiday apartment can accommodate up to 4 guests. Situated in Murviel-lès-Béziers, a beautiful village offering all amenities, and only 12km from the historical city of Béziers, renowned for its basilica and its floodgates on the Canal du Midi. Narbonne is 50km away and has a cathedral dating from 1272, an archaeological museum, the Archbishops' Palace and an indoor market. The Mediterranean Sea and its sandy beaches are 25km away. For golf enthusiasts, there is a course 16km from the property. Shop and restaurant 1km, beach 25km.
All on first floor: Lounge/kitchen/diner, shower room with toilet and basin, 2 double bedrooms.
Electric heating, cot, highchair, colour TV (French channels only), wi-fi, washing machine, dishwasher, microwave, balcony, garage parking for 1 car. Sorry, no pets. No smoking please. NB: External steps to entrance.
This holiday flat, one of four is located in the heart of the town and is therefore just a stone throw from the shops and local market. The original and very inviting resort has maintained the architecture famous for the region, Provence. Here you have free facilities: lift, wireless internet connection (at the reception) as well as covered parking space. Furthermore there are plenty of activities that you can take part in for a fee: climbing, amusement park, horseriding, excursions to the mountains, hiking, paragliding, sightseeing flight as well as mountainbiking, kayaking, go-karting and quadbiking. The apartment benefits from a shared outdoor swimming pool, which you can relax in after a long day exploring this beautiful region. Shop 500m.
Lounge/kitchen/diner, bathroom with toilet and basin, 1 double bedroom, sofa bed in lounge.
Dishwasher, shared garden, terrace, garden furniture, off road parking. Sorry, no pets.
This wonderful air-conditioned villa with private terrace is in the heart of the Cathar country. Here, you will discover well preserved ruins, numerous castles as well as the region's turbulent history. If you go to the castle of Puilaurens, an impressive fortress perched on a rock peak, you will discover an exceptional panoramic view and you shiver hearing the story of the Dame Blanche (White lady) who is believed to wander along the ramparts when the moon is full. In the castle of Peyrepertuse, nicknamed celestial Carcassonne due to its vertiginous height, you will discover Saint Jordi's donjon, an unusual small internal castle. The beautiful abbeys of Saint Hilaire and Fontfroide and the village of books and graphic arts, Montolieu, are also worth a visit. Sports enthusiasts will be pleased with the many activities on offer in this beautiful region: cycle along the Canal-du-Midi, canoe, raft or hydro speed in the Gorges of Pierre Lys and even go canyoning in the Gorges of Galamus. You can also try the treetop adventure park of Alet or if you would rather relax and unwind then you'll find plenty of places to sit and fish in the surrounding lakes and rivers. It is impossible not to taste the local culinary specialities such as cassoulet and the garriguet, the cake of the Cathar country, without forgetting a local Corbières wine. A trip to Narbonne and its beaches 75km away can, also be something for you to do during your stay in the Aude, where this beautiful holiday rental waits for you. The city of Carcassonne is only 6km away and restaurants and shops are located 300m away from the property. Shop and restaurant 300m.
Lounge/kitchen/diner. Bathroom with toilet and basin. 2 double bedrooms.
Electric heating. Cot. Highchair. Wi-fi. Washing machine. Dishwasher. Fridge. Microwave. Garden. Terrace. Garden furniture. Barbecue. On road parking. Sorry, no pets. No smoking please. NB: Step to terrace.
Located in the village of Le Grau-du-Roi, this first floor studio apartment is conveniently located 600m away from the sandy beach and the Mediterranean sea. You will enjoy the on-site shared swimming pool (48m², open Jun-Sep), as well as being just 20m away from the nearest shops. From here, visit Aigues-Mortes, 6km, Montpellier, 35km, and Nîmes, 50km.
Lounge/kitchen/diner, shower room with toilet and basin, bunk bed in hallway, sofa bed in lounge.
Electric heating, colour TV (French channels only), microwave, terrace, outdoor furniture, on street parking. Sorry, no pets. No smoking please.
This quirky air conditioned property is situated 22km from the sea and the beautiful beaches of Languedoc, amid the alfalfa fields where horses graze freely. It features a sunny terrace on a private, enclosed plot with a barbecue and access to a lovely shared outdoor swimming pool (36m², open mid Apr-Sep) 150m away in the owners grounds. Discover the beautiful Camargue Regional Park with its great range of fauna and flora, or why not explore the beautiful Alpilles region, dominated by the Chateau of Les Baux de Provence? The beautiful Pont du Gard and river cruises on the Canal du Midi are worth visiting. Don't forget to stop off at the small walled, medieval city of Aigues Mortes renowned for its food and culture. Shop and restaurant 1km, beach 22km.
All on ground floor: Lounge/kitchen/diner, shower room with toilet and basin, double bed and double sofa bed in lounge.
Electric heating, cot, washing machine, fridge, freezer, microwave, lawned garden, terrace, garden furniture, barbecue, off road parking for 3 cars. Up to 2 pets welcome.
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cottages.com is the new home of cottages4you (Cottages for You).
cottages.com is a trading name of Wyndham Vacation Rentals (UK) Ltd. Registered in England and Wales.
Registered Office: Spring Mill, Stoney Bank Road, Earby, Lancashire,BB94 0AA, UK
Company Registration Number 00965389. VAT Registration Number: GB 598 22 99 77


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Tiger Woods PGA TOUR 11 - quick play preview
Tiger Woods PGA TOUR 11 is one of the new wave of games that will use the PlayStation Move controller when it comes out in the US and the UK in September. While you'll be able to get the game before then, we checked out the new motion controller with the game to see how the action faired. Will you be wanting to get the extras come autumn? Read on to find out.
Tiger Woods PGA TOUR 11
What platform is it on?
PS3, Xbox 360, Nintendo Wii
When's it due out?
Now in the US, July in the UK, PlayStation Move update promised for September
What other game is it like?
Any other golf game you've played, Tiger Woods PGA TOUR 10
Does it use any new tech?
Yep, PlayStation Move, although you don't need it to play
The pitch
Tiger Woods PGA TOUR 11 lets players fight for honour and their country in the all-new Ryder Cup Challenge at the Twenty Ten Course at Celtic Manor Resort; the course of the 2010 Ryder Cup as well as play stacks of courses as one of the world's leading golfers - Tiger Woods
The storyline
You play Tiger Woods strutting his stuff on the golf course, not in the bedroom.
Our first impressions
Tiger Woods from EA, like Heavy Rain, is one game that will be getting an update to give it access to the PlayStation Move controller when it comes out in November and if you're a golfing pro it is highly recommended that you do.
Not one to mess around with easy levels we dived straight into the expert level with zero assistance and zero help from the computer. We had assistance from the product manager though who cringed at our gameplay tactics. We wanted it real. The problem is (we don't play golf that much) that's exactly what you'll get.
Five holes and 15 over par later and we've lived to tell the tale, just. Using a single Move controller you hold it like it's a club and then are left to master your stroke. How you swing is exactly replicated on screen for better or for worse. That means if you slice it in real life, you've sliced it in-game. If you swing hard it will swing hard in the game. If you ... well you get the picture.
The Move controller basically allows you to play as good as you can in real life. It is that simple. Thankfully you can tone it down, you can get it to help you, you can set it so you hit a perfect shot every time.
There is also the option to not use the PlayStation Move controller at all, although with the ability to up your game so much we would highly recommend it when it comes out later this year.
Please note
The E3 games convention is a fantastic chance to see the latest games due out over the coming year, as well as, letting us get a glimpse into what is going to be the big titles and the ones to avoid like the plague.
The big problem however is that for most of the titles that glimpse is, well, just that. At the show you'll get to play a level here or a multiplayer map there.
So with that in mind we present you with our Quick Play.
What we've done is broken down the key facts you need to know and then given you our first impressions based on around 15 minutes of gaming. For us that 15 minutes isn't enough to do a First Look review. How can you rate a game that offers over 30 hours of gaming on just 15 minutes of play? However it should hopefully give you an idea, a feeling, a notion, of what to expect come launch day.
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