an increase in sympathetic activity has been generally reported to have an intimate 
 relation with the trigger and exacerbation of hypertension1,2,3 . understanding hypertension and its mechanisms is very important in 
 specialized cardiovascular physiotherapy2 , 4 , 5 . the development of hypertension is also associated with altered vascular reactivity and 
 increased transmural pressure or stretch , which directly affects vascular smooth muscle 
 cells6,7,8,9 . the 
 vascular smooth muscle is an important effector in the regulation of vasomotor tone6 , 8 . in 
 particular , a structural and functional impairment in the regulation of vascular smooth 
 muscle contraction may be important in the pathogenesis and maintenance of increased 
 peripheral vascular resistance in hypertension5 , 6 , 8 . 
 the total peripheral resistance and the vascular reactivity to contractile agonists are 
 increased in patients and experimental animal models with essential and secondary 
 hypertension5 , 6 , 8 . various experimental 
 animal models have been used in the research of the pathophysiology of hypertension . spontaneously hypertensive rats have been widely used as a pathophysiological animal model 
 of genetically linked hypertension such as a human essential hypertension8 . the dahl salt - sensitive rat was developed 
 by selective breeding of rats for sensitivity or resistance to the hypertensive effects of a 
 high salt diet10 , and the first 
 experimental model of renovascular hypertension via a two - kidney , one clip maneuver 
 demonstrated that renal ischemia is the cause of this disease11 . specifically , the deoxycorticosterone acetate ( doca)-salt 
 hypertensive models , models of volume - expanded hypertension , were used to describe the 
 natural history of malignant hypertension and the biochemical and hormonal characteristics 
 of each stage of the disease5,6,7 , 12 , 13 . the purpose of this 
 review was to collate the body of knowledge on doca - salt hypertension and the signal 
 transduction involved in order to prepare a basic reference for cardiovascular physiotherapy 
 research . one cause of hypertension is generally excessive salt consumption in conjunction with 
 stress , which has a direct correlation with the doca - salt hypertensive model1 , 2 , 5 . in reality , when an increase in blood 
 pressure occurs , the blood flow and volume are elevated by retention of water and sodium 
 in the renal tubule , which is affected by the renin - angiotensin - aldosterone axis exposure 
 to chronic stress1 , 2 , 5 , 6 . in our experimental process , which was in accordance with the 
 guide for the care and use of laboratory animals published by the us national institutes 
 of health ( nih publication no . 85 - 23 , revised 1996 ) , the animals underwent uninephrectomy 
 via flank incision under intramuscular anesthesia5,6,7 ( fig . 1.schematic representation of deoxycorticosterone acetate - salt hypertension - induced 
 responses and cardiovascular physiotherapy sd : sprague - dawley rats ; sham : 
 sham - operated normotensive rats ; doca : deoxycorticosterone acetate - salt hypertensive 
 rats ; n : nephrectomy ; nts : necrotic tissues ; cca : common carotid artery ; sp and dp : 
 systolic and diastolic blood pressure ; cw : circulating water ; wo : wash out ; s : 
 sample ; pss : physiological salt solution ; [ ca]i : 
 intracellular or cytosolic ca ; r340/380 : ratio of fluorescence at the 
 wavelengths of 340 and 380  nm ; kv current : voltage - dependent k current ; 
 pss : physiological salt solution ; mesenteric a. : mesenteric artery ; et-1 : 
 endothelin-1 ; eta : subtype a of endothelin receptor ; erk1/2 : 
 extracellular signal - regulated protein kinase 1 and 2 ; p38mapk : p38 
 mitogen - activated protein kinase ; sapk / jnk : stress - activated protein kinase / c - jun 
 nh2-terminal kinase ; mlck : myosin light chain kinase ; pkc : protein 
 kinase c ; rock : rho - associated coiled coil - forming protein kinase ; pi3  k : 
 phosphatidylinositide-3 kinase ; mapk : mitogen - activated protein kinase ; et - acu : 
 electroacupuncture ) . the adrenal glands of both sham - operated rat and doca - salt hypertensive rat were 
 not removed because adrenalectomy prevents the development of hypertension14 . after doca implantation surgery , 
 doca - salt hypertensive rats received 0.9% nacl plus 0.2% kcl drinking solution ( table 1table 1.the characteristics of deoxycorticosterone acetate - salt hypertensive 
 ratsvariablenormotensive controldoca - salt hypertensive ratsreferencesbody weight ( g)256  18 to 437  8204  18 to 345  812 , 23 , 43 , 45 , 47 , 48 , 50,51,524 weeks sbp ( mmhg)109  4 to 141  6184  2 to 225  65 , 23 , 43 , 46,47,48,49,50,51,52mcfp ( mmhg)6.7  0.48.0  0.450heart rate ( b / m)379  13 to 426  13370  10 to 432  1550 , 51aortic weight ( mg / cm)9.7  0.2 to 11.2  0.313.0  0.6 to 12.9  0.543 , 52wall thickness ( m)123  2 to 142  4149  5 to 190  343 , 52wall area ( mm)0.676  0.0150.853  0.03343wall - to - lumen ratio0.324  0.0040.401  0.01643media thickness ( m)10.8  0.716.0  1.044media - lumen ratio ( % ) 4.7  0.37.4  0.444media csa ( m)8,230  701 to 8,657  62611,879  1,327 to 14,475  3,12344 , 45aortic csa ( mm)3.8  0.64.8  0.447lumen diameter ( m)230.6  6.7217.9  12.543femoral ring weight ( mg)0.2154  0.00560.2279  0.006223heart weight ( g)0.995  0.02 to 1.22  0.091.329  0.02 to 1.42  0.0744 , 45heart weight ( mg/100  g bw)275.79  6.68392.73  14.5123hw / bw ( g / kg)2.91  0.063.62  0.0943heart weight ( % /tbw)0.35  0.020.51  0.0112lv weight ( g)0.84  0.061.02  0.0645rv weight ( g)0.19  0.010.21  0.0245vw - to - bw ratio ( g / kg)3.3  0.14.5  0.149kidney weight ( g)3.7  0.24.5  0.345kidney weight ( % /tbw)0.65  0.020.92  0.0412lkw / bw ( g / kg)5.23  0.108.20  0.2143values are % /tbw indicates the % of total body weight ; sbp : systolic 
 blood pressure ; mcfp : mean circulatory filling pressure ; bw : body weight ; hw : heart 
 weight ; vw - to - bw ratio : ventricular weight - to - body weight ratio ; lkw : left kidney 
 weight ; csa : cross - sectional area , fig . induction of doca - salt hypertension is directly related to the 
 increased vascular resistance that is widely known to be caused by an increase in vessel 
 wall tension or other factors related to tension ( fig . 
 1 ) , such as mitogen - activated protein kinase ( mapk ) , protein tyrosine kinase 
 ( ptk ) , protein kinase c ( pkc ) , phosphoinositide 3-kinase ( pi3  k ) and rho - associated coiled 
 coil - forming protein kinase ( rock)5,6,7,8,9 . 
 in particular , activation of mapk is essential for the increase of muscle contraction and 
 elevation of blood pressure5,6,7 . meanwhile , 
 several previous studies have indicated that electrical stimulation , massage , moxibustion , 
 medicinal herbs such as ligusticum wallichii and cordycepin and electroacupuncture may be 
 used as alternative therapies for hypertension1 , 
 2 , 15,16,17,18,19 in particular , but more systematic and scientific physiotherapy 
 studies are still needed4 ( fig . schematic representation of deoxycorticosterone acetate - salt hypertension - induced 
 responses and cardiovascular physiotherapy sd : sprague - dawley rats ; sham : 
 sham - operated normotensive rats ; doca : deoxycorticosterone acetate - salt hypertensive 
 rats ; n : nephrectomy ; nts : necrotic tissues ; cca : common carotid artery ; sp and dp : 
 systolic and diastolic blood pressure ; cw : circulating water ; wo : wash out ; s : 
 sample ; pss : physiological salt solution ; [ ca]i : 
 intracellular or cytosolic ca ; r340/380 : ratio of fluorescence at the 
 wavelengths of 340 and 380  nm ; kv current : voltage - dependent k current ; 
 pss : physiological salt solution ; mesenteric a. : mesenteric artery ; et-1 : 
 endothelin-1 ; eta : subtype a of endothelin receptor ; erk1/2 : 
 extracellular signal - regulated protein kinase 1 and 2 ; p38mapk : p38 
 mitogen - activated protein kinase ; sapk / jnk : stress - activated protein kinase / c - jun 
 nh2-terminal kinase ; mlck : myosin light chain kinase ; pkc : protein 
 kinase c ; rock : rho - associated coiled coil - forming protein kinase ; pi3  k : 
 phosphatidylinositide-3 kinase ; mapk : mitogen - activated protein kinase ; et - acu : 
 electroacupuncture values are means  se . % /tbw indicates the % of total body weight ; sbp : systolic 
 blood pressure ; mcfp : mean circulatory filling pressure ; bw : body weight ; hw : heart 
 weight ; vw - to - bw ratio : ventricular weight - to - body weight ratio ; lkw : left kidney 
 weight ; csa : cross - sectional area it has been widely reported that hypertension is characterized by an increased 
 responsiveness to vasoconstrictor agonists5 , 7 , 12 . in previous studies , specifically , the doca - salt hypertensive model is associated with marked changes that 
 regulate vascular smooth muscle contraction due to increased adrenoceptor reactivity and 
 activation of the sympathetic nervous system21 . actually , the responsiveness of vasculature to norepinephrine is 
 increased in doca - salt hypertension22 , 23 . 5-hydroxytryptamine markedly increases 
 when contractions are stimulated in vascular smooth muscle strips isolated from animal 
 models of experimental and/or genetic hypertension compared with normotensive animals24 , 25 . furthermore , one of our previous studies was the first to 
 demonstrate that vasoconstrictors such as endothelin-1 ( et-1 ) decreased muscle 
 contractility and the activity of p38 mapk in aortic smooth muscle from doca - salt 
 hypertensive rats compared with normotensive rats5 . these results imply that the mapk pathway plays a central role in 
 the control of muscle contraction and doca - salt hypertension5 , 22 . epidermal growth 
 factor ( egf ) , one of the various growth factors , is an important regulator of cell 
 regulation in a variety of cells7 , 26 . egf , a mitogenic polypeptide with a 
 molecular weight of approximately 6 kd , is excreted in human urine in nanomolar 
 quantities26 . egf , once released , can bind to its receptors found on vascular 
 smooth muscle cells , in the submandibular gland , and in the rat liver30 . although egf acting via its tyrosine kinase receptor is 
 widely recognized for its mitogenic and acid - inhibitory activity31 , it is now appreciated that this peptide can also 
 modulate the contractility of a variety of smooth muscle cells and is related to the 
 hypertension7 , 32 , 33 . in kinase - inactive 
 mutants , egf directly activates hypertension - related mapk family members34 . the major findings of one of our 
 previous studies were that egf contracts aortic smooth muscle from doca - salt hypertensive 
 rats but not sham - operated rats and that egf increases the activity of mapk in doca - salt 
 hypertensive rats7 . these findings 
 indicate that significant changes in egf responsiveness occur during the development of 
 hypertension and may allow for the development of a contractile response to egf . moreover , 
 the egf receptor is activated and is capable of interacting with proteins , including grb2 , 
 guanine nucleotide exchange factor sos , shc , c - src , ras and raf-1 , leading to activation 
 of the tyrosine kinase - dependent mapk pathway35 . however , in one of our previous studies , inhibition of the pi3  k 
 pathway , but not rock , attenuated egf - induced muscle contraction and mapk activation but 
 not sapk / jnk in doca - salt hypertension . furthermore , understanding the mechanisms of 
 growth factor - induced contraction should be a critical issue in cardiovascular 
 physiotherapy4 . in this review , 1 ) . when scientific studies are performed in the fields of 
 thermo- , hydro- , and electrotherapy , neurophysiotherapy , manipulative therapy , and 
 therapeutic massage , we expect remarkable growth both in research and clinical 
 applications in the field of cardiovascular physiotherapy36,37,38,39,40,41,42 ( fig . one cause of hypertension is generally excessive salt consumption in conjunction with 
 stress , which has a direct correlation with the doca - salt hypertensive model1 , 2 , 5 . in reality , when an increase in blood 
 pressure occurs , the blood flow and volume are elevated by retention of water and sodium 
 in the renal tubule , which is affected by the renin - angiotensin - aldosterone axis exposure 
 to chronic stress1 , 2 , 5 , 6 . in our experimental process , which was in accordance with the 
 guide for the care and use of laboratory animals published by the us national institutes 
 of health ( nih publication no . 85 - 23 , revised 1996 ) , the animals underwent uninephrectomy 
 via flank incision under intramuscular anesthesia5,6,7 ( fig . 1.schematic representation of deoxycorticosterone acetate - salt hypertension - induced 
 responses and cardiovascular physiotherapy sd : sprague - dawley rats ; sham : 
 sham - operated normotensive rats ; doca : deoxycorticosterone acetate - salt hypertensive 
 rats ; n : nephrectomy ; nts : necrotic tissues ; cca : common carotid artery ; sp and dp : 
 systolic and diastolic blood pressure ; cw : circulating water ; wo : wash out ; s : 
 sample ; pss : physiological salt solution ; [ ca]i : 
 intracellular or cytosolic ca ; r340/380 : ratio of fluorescence at the 
 wavelengths of 340 and 380  nm ; kv current : voltage - dependent k current ; 
 pss : physiological salt solution ; mesenteric a. : mesenteric artery ; et-1 : 
 endothelin-1 ; eta : subtype a of endothelin receptor ; erk1/2 : 
 extracellular signal - regulated protein kinase 1 and 2 ; p38mapk : p38 
 mitogen - activated protein kinase ; sapk / jnk : stress - activated protein kinase / c - jun 
 nh2-terminal kinase ; mlck : myosin light chain kinase ; pkc : protein 
 kinase c ; rock : rho - associated coiled coil - forming protein kinase ; pi3  k : 
 phosphatidylinositide-3 kinase ; mapk : mitogen - activated protein kinase ; et - acu : 
 electroacupuncture ) . the adrenal glands of both sham - operated rat and doca - salt hypertensive rat were 
 not removed because adrenalectomy prevents the development of hypertension14 . after doca implantation surgery , 
 doca - salt hypertensive rats received 0.9% nacl plus 0.2% kcl drinking solution ( table 1table 1.the characteristics of deoxycorticosterone acetate - salt hypertensive 
 ratsvariablenormotensive controldoca - salt hypertensive ratsreferencesbody weight ( g)256  18 to 437  8204  18 to 345  812 , 23 , 43 , 45 , 47 , 48 , 50,51,524 weeks sbp ( mmhg)109  4 to 141  6184  2 to 225  65 , 23 , 43 , 46,47,48,49,50,51,52mcfp ( mmhg)6.7  0.48.0  0.450heart rate ( b / m)379  13 to 426  13370  10 to 432  1550 , 51aortic weight ( mg / cm)9.7  0.2 to 11.2  0.313.0  0.6 to 12.9  0.543 , 52wall thickness ( m)123  2 to 142  4149  5 to 190  343 , 52wall area ( mm)0.676  0.0150.853  0.03343wall - to - lumen ratio0.324  0.0040.401  0.01643media thickness ( m)10.8  0.716.0  1.044media - lumen ratio ( % ) 4.7  0.37.4  0.444media csa ( m)8,230  701 to 8,657  62611,879  1,327 to 14,475  3,12344 , 45aortic csa ( mm)3.8  0.64.8  0.447lumen diameter ( m)230.6  6.7217.9  12.543femoral ring weight ( mg)0.2154  0.00560.2279  0.006223heart weight ( g)0.995  0.02 to 1.22  0.091.329  0.02 to 1.42  0.0744 , 45heart weight ( mg/100  g bw)275.79  6.68392.73  14.5123hw / bw ( g / kg)2.91  0.063.62  0.0943heart weight ( % /tbw)0.35  0.020.51  0.0112lv weight ( g)0.84  0.061.02  0.0645rv weight ( g)0.19  0.010.21  0.0245vw - to - bw ratio ( g / kg)3.3  0.14.5  0.149kidney weight ( g)3.7  0.24.5  0.345kidney weight ( % /tbw)0.65  0.020.92  0.0412lkw / bw ( g / kg)5.23  0.108.20  0.2143values are % /tbw indicates the % of total body weight ; sbp : systolic 
 blood pressure ; mcfp : mean circulatory filling pressure ; bw : body weight ; hw : heart 
 weight ; vw - to - bw ratio : ventricular weight - to - body weight ratio ; lkw : left kidney 
 weight ; csa : cross - sectional area , fig . induction of doca - salt hypertension is directly related to the 
 increased vascular resistance that is widely known to be caused by an increase in vessel 
 wall tension or other factors related to tension ( fig . 
 1 ) , such as mitogen - activated protein kinase ( mapk ) , protein tyrosine kinase 
 ( ptk ) , protein kinase c ( pkc ) , phosphoinositide 3-kinase ( pi3  k ) and rho - associated coiled 
 coil - forming protein kinase ( rock)5,6,7,8,9 . 
 in particular , activation of mapk is essential for the increase of muscle contraction and 
 elevation of blood pressure5,6,7 . meanwhile , 
 several previous studies have indicated that electrical stimulation , massage , moxibustion , 
 medicinal herbs such as ligusticum wallichii and cordycepin and electroacupuncture may be 
 used as alternative therapies for hypertension1 , 
 2 , 15,16,17,18,19 in particular , but more systematic and scientific physiotherapy 
 studies are still needed4 ( fig . schematic representation of deoxycorticosterone acetate - salt hypertension - induced 
 responses and cardiovascular physiotherapy sd : sprague - dawley rats ; sham : 
 sham - operated normotensive rats ; doca : deoxycorticosterone acetate - salt hypertensive 
 rats ; n : nephrectomy ; nts : necrotic tissues ; cca : common carotid artery ; sp and dp : 
 systolic and diastolic blood pressure ; cw : circulating water ; wo : wash out ; s : 
 sample ; pss : physiological salt solution ; [ ca]i : 
 intracellular or cytosolic ca ; r340/380 : ratio of fluorescence at the 
 wavelengths of 340 and 380  nm ; kv current : voltage - dependent k current ; 
 pss : physiological salt solution ; mesenteric a. : mesenteric artery ; et-1 : 
 endothelin-1 ; eta : subtype a of endothelin receptor ; erk1/2 : 
 extracellular signal - regulated protein kinase 1 and 2 ; p38mapk : p38 
 mitogen - activated protein kinase ; sapk / jnk : stress - activated protein kinase / c - jun 
 nh2-terminal kinase ; mlck : myosin light chain kinase ; pkc : protein 
 kinase c ; rock : rho - associated coiled coil - forming protein kinase ; pi3  k : 
 phosphatidylinositide-3 kinase ; mapk : mitogen - activated protein kinase ; et - acu : 
 electroacupuncture values are means  se . % /tbw indicates the % of total body weight ; sbp : systolic 
 blood pressure ; mcfp : mean circulatory filling pressure ; bw : body weight ; hw : heart 
 weight ; vw - to - bw ratio : ventricular weight - to - body weight ratio ; lkw : left kidney 
 weight ; csa : cross - sectional area it has been widely reported that hypertension is characterized by an increased 
 responsiveness to vasoconstrictor agonists5 , 7 , 12 . in previous studies , specifically , the doca - salt hypertensive model is associated with marked changes that 
 regulate vascular smooth muscle contraction due to increased adrenoceptor reactivity and 
 activation of the sympathetic nervous system21 . actually , the responsiveness of vasculature to norepinephrine is 
 increased in doca - salt hypertension22 , 23 . 5-hydroxytryptamine markedly increases 
 when contractions are stimulated in vascular smooth muscle strips isolated from animal 
 models of experimental and/or genetic hypertension compared with normotensive animals24 , 25 . furthermore , one of our previous studies was the first to 
 demonstrate that vasoconstrictors such as endothelin-1 ( et-1 ) decreased muscle 
 contractility and the activity of p38 mapk in aortic smooth muscle from doca - salt 
 hypertensive rats compared with normotensive rats5 . these results imply that the mapk pathway plays a central role in 
 the control of muscle contraction and doca - salt hypertension5 , 22 . epidermal growth 
 factor ( egf ) , one of the various growth factors , is an important regulator of cell 
 regulation in a variety of cells7 , 26 . egf , a mitogenic polypeptide with a 
 molecular weight of approximately 6 kd , is excreted in human urine in nanomolar 
 quantities26 . egf , once released , can bind to its receptors found on vascular 
 smooth muscle cells , in the submandibular gland , and in the rat liver30 . although egf acting via its tyrosine kinase receptor is 
 widely recognized for its mitogenic and acid - inhibitory activity31 , it is now appreciated that this peptide can also 
 modulate the contractility of a variety of smooth muscle cells and is related to the 
 hypertension7 , 32 , 33 . in kinase - inactive 
 mutants , egf directly activates hypertension - related mapk family members34 . the major findings of one of our 
 previous studies were that egf contracts aortic smooth muscle from doca - salt hypertensive 
 rats but not sham - operated rats and that egf increases the activity of mapk in doca - salt 
 hypertensive rats7 . these findings 
 indicate that significant changes in egf responsiveness occur during the development of 
 hypertension and may allow for the development of a contractile response to egf . moreover , 
 the egf receptor is activated and is capable of interacting with proteins , including grb2 , 
 guanine nucleotide exchange factor sos , shc , c - src , ras and raf-1 , leading to activation 
 of the tyrosine kinase - dependent mapk pathway35 . however , in one of our previous studies , inhibition of the pi3  k 
 pathway , but not rock , attenuated egf - induced muscle contraction and mapk activation but 
 not sapk / jnk in doca - salt hypertension . furthermore , understanding the mechanisms of 
 growth factor - induced contraction should be a critical issue in cardiovascular 
 physiotherapy4 . in this review , 1 ) . when scientific studies are performed in the fields of 
 thermo- , hydro- , and electrotherapy , neurophysiotherapy , manipulative therapy , and 
 therapeutic massage , we expect remarkable growth both in research and clinical 
 applications in the field of cardiovascular physiotherapy36,37,38,39,40,41,42 ( fig .
[ purpose ] the purpose of this review was to elucidate the deoxycorticosterone acetate 
 ( doca)-salt - related hypertensive mechanism and to contribute to future studies of 
 cardiovascular physiotherapy . 
 [ methods ] this paper focuses on the signal transductions 
 that control hypertension and its mechanisms . we include results reported by our 
 laboratory in a literature review . [ results ] our results and the literature show the 
 various mechanisms of doca - salt hypertension . 
 [ conclusion ] in this review paper , we 
 carefully discuss the signal transduction in hypertension based on our studies and with 
 reference to cardiovascular physiotherapy research .