Salt-loaded Dahl Salt-sensitive Rats Research Articles

Association of Antihypertensive Effects of Esaxerenone with the Internal Sodium Balance in Dahl Salt-Sensitive Hypertensive Rats.

Background: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). Objective: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. Methods: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. Results: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. Conclusions: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats.

PGI2 Analog Attenuates Salt-Induced Renal Injury through the Inhibition of Inflammation and Rac1-MR Activation.

Renal inflammation is known to be involved in salt-induced renal damage, leading to end-stage renal disease. This study aims to evaluate the role of inflammation in anti-inflammatory and renoprotective effects of beraprost sodium (BPS), a prostaglandin I2 (PGI2) analog, in Dahl salt-sensitive (DS) rats. Five-week-old male DS rats were fed a normal-salt diet (0.5% NaCl), a high-salt diet (8% NaCl), or a high-salt diet plus BPS treatment for 3 weeks. BPS treatment could inhibit marked proteinuria and renal injury in salt-loaded DS rats with elevated blood pressure, accompanied by renal inflammation suppression. Notably, high salt increased renal expression of active Rac1, followed by increased Sgk1 expressions, a downstream molecule of mineralocorticoid receptor (MR) signal, indicating salt-induced activation of Rac1-MR pathway. However, BPS administration inhibited salt-induced Rac1-MR activation as well as renal inflammation and damage, suggesting that Rac1-MR pathway is involved in anti-inflammatory and renoprotective effects of PGI2. Based upon Rac1 activated by inflammation, moreover, BPS inhibited salt-induced activation of Rac1-MR pathway by renal inflammation suppression, resulting in the attenuation of renal damage in salt-loaded DS rats. Thus, BPS is efficacious for the treatment of salt-induced renal injury.

Endogenous Cardiotonic Steroids and Differential Patterns of Sodium Pump Inhibition in NaCl-Loaded Salt-Sensitive and Normotensive Rats

Endogenous sodium pump inhibitors promote sodium excretion in normotensives and contribute to vasoconstriction in NaCl-sensitive hypertension. Marinobufagenin (MBG), an endogenous bufadienolide inhibitor of alpha-1 sodium pump, contributes to hypertension in Dahl salt-sensitive rats (DS). We hypothesized that in NaCl-loaded DS and normotensive Sprague-Dawley rats (S-D), MBG would elicit different patterns of sodium pump inhibition. We compared systolic blood pressure (SBP), renal sodium excretion, activity of the sodium pump in aorta and renal medulla, and levels of MBG, atrial natriuretic peptide (ANP), and cyclic guanosine monophosphate (cGMP) in salt-loaded DS and S-D (20% NaCl, 2.5 ml/kg, intraperitoneally). NaCl loading produced sustained elevations in renal MBG excretion in both DS (2.41 +/- 0.24 vs. 0.79 +/- 0.08 pmol/h/kg, P < 0.01) and S-D (1.97 +/- 0.37 vs. 0.60 +/- 0.07 pmol/h/kg, P < 0.01) vs. that at baseline (n = 10 for each group). In NaCl-loaded DS, SBP rose by 18 mm Hg (P < 0.01) and aortic sodium pump was inhibited by 22% (P < 0.05 vs. control), while in S-D, SBP and activity of aortic sodium pump did not change. NaCl-loaded S-D excreted twice as much sodium as DS; in S-D, renal sodium pump was inhibited by 24% vs. 14% inhibition in DS (P < 0.05). NaCl loading elicited increases in plasma ANP and in renal cGMP excretion in S-D but not in DS. Our present observations demonstrate that in NaCl-loaded S-D and DS, a comparable MBG response is associated with preferential inhibition of the sodium pump in the kidney and in vascular smooth muscle, respectively, resulting in an adaptive natriuresis in S-D but sodium retention and pressor response in DS.

Protective Effect of Dietary Potassium Against Vascular Injury in Salt-Sensitive Hypertension

Hypertensive cardiovascular damage is accelerated by salt loading but counteracted by dietary potassium supplementation. We suggested recently that antioxidant actions of potassium contribute to protection against salt-induced cardiac dysfunction. Therefore, we examined whether potassium supplementation ameliorated cuff-induced vascular injury in salt-sensitive hypertension via suppression of oxidative stress. Four-week-old Dahl salt-sensitive rats were fed a normal-salt (0.3% NaCl), high-salt (8% NaCl), or high-salt plus high-potassium (8% KCl) diet for 5 weeks, and some of the rats fed a high-salt diet were also given antioxidants. One week after the start of the treatments, a silicone cuff was implanted around the femoral artery. Examination revealed increased cuff-induced neointimal proliferation with adventitial macrophage infiltration in arteries from salt-loaded Dahl salt-sensitive rats compared with that in arteries from non-salt-loaded animals (intima/media ratio: 0.471+/-0.070 versus 0.302+/-0.037; P<0.05), associated with regional superoxide overproduction and reduced nicotinamide-adenine dinucleotide phosphate oxidase activation and mRNA overexpression. On the other hand, simultaneous potassium supplementation attenuated salt-induced neointimal hyperplasia (intima/media ratio: 0.205+/-0.012; P<0.001), adventitial macrophage infiltration, superoxide overproduction, and reduced nicotinamide-adenine dinucleotide phosphate oxidase activation and overexpression. Antioxidants, which decrease vascular oxidative stress, also reduced neointima formation induced by salt excess. In conclusion, high-potassium diets seems to have a protective effect against the development of vascular damage induced by salt loading mediated, at least in part, through suppression of the production of reactive oxygen species probably generated by reduced nicotinamide-adenine dinucleotide phosphate oxidase.

Podocyte Injury Underlies the Glomerulopathy of Dahl Salt-Hypertensive Rats and Is Reversed by Aldosterone Blocker

Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

The protective effects of taurine against renal damage by salt loading in Dahl salt-sensitive rats.

We evaluated whether taurine prevents renal damage which is accompanied with enhanced expression of lectin-like oxidized low-density lipoprotein (OxLDL) receptor-1 (LOX-1) mRNA, in salt-loaded Dahl salt-sensitive (DS) rats. Male, 4-week-old DS rats were fed on either a high-salt (8% NaCl) or normal-salt (0.66% NaCl) diet for 4 weeks. Some DS rats with high-salt diet were given drinking water containing 1% taurine. We evaluated blood pressure, renal function, renal LOX-1 expression and parameters for oxidative stress. In salt-loaded DS rats, there was a significant increase in heart weight and urinary protein, accompanied with enhanced LOX-1 expression in kidney. All of these were reduced by concomitant supplementation of taurine, although both antihypertensive and antihyperlipidemic effects of taurine were only slight in salt-loaded DS rats. On the other hand, salt-induced increment in urinary 8-hydroxy-deoxyguanosine, a parameter of oxidative damage, was completely normalized by taurine supplementation. The protective effects of taurine supplementation against renal damage induced by salt loading in DS rats may be attributed to the suppression of LOX-1, probably through its antioxidant effects.

Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859.

To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-1 05859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential of this compound as an ETA antagonist Vehicle and J-105859 were administered to salt-loaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-1 05859. The Ki values of J-1 05859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-1 05859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-1 05859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-1 05859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

Oestrogen attenuates the increases in blood pressure and platelet aggregation in ovariectomized and salt-loaded Dahl salt-sensitive rats

To investigate the effects of oestrogen supplementation after ovariectomy on systolic blood pressure and platelet aggregation on different sodium content diet in the female Dahl salt-sensitive rats. At 12 weeks of age, rats were ovariectomized or sham-operated and were fed either a high NaCl (8%) or low NaCl (0.3%) diet Ovariectomized rats were treated with either 17beta-oestradiol or placebo for 8 weeks, whereas sham-operated rats received placebo alone. After 8 weeks, the systolic blood pressure and platelet aggregation were measured and analysed by two-way analysis of variance. The systolic blood pressure of ovariectomized rats was significantly higher than that of sham-operated rats, and this increase in systolic blood pressure was suppressed by oestrogen supplementation. Systolic blood pressure was inversely correlated with plasma 17beta-oestradiol levels (r= -0.77, P< 0.01) and with the uterus weight to body weight ratio (r = -0.47, P < 0.01). Platelet aggregation was significantly enhanced by salt loading. Salt loading and female hormonal manipulation significantly interacted on platelet aggregation. Only in Dahl salt-sensitive rats fed a low sodium diet, ovariectomy increased platelet aggregation, whereas hormone replacement did not improve it. In Dahl salt-sensitive rats fed a high sodium diet, hormone replacement reduced platelet aggregation. Oestrogen replacement suppresses the development of hypertension and attenuates platelet aggregatory function in the salt-loaded ovariectomized Dahl salt-sensitive rats. It has a potential to inhibit the atherosclerotic process in postmenopausal hypertension.

Potassium Supplementation Increases Sodium Excretion and Nitric Oxide Production in Hypertensive Dahl Rats

The present study was designed to investigate whether antihypertensive and natriuretic effects of K were achieved by elevation of nitric oxide (NO) production in Dahl salt-sensitive (DS) rats. The rats were placed in individual metabolic cage and fed a high sodium diet with or without K supplementation for 4 weeks. K supplementation counteracted the blood-pressure raising effect of NaCl. K supplementation significantly enhanced sodium excretion and reduced sodium retention, increased the urinary nitrite plus nitrate excretion and kidney constitutive NO synthase activity in salt-loaded DS rats. These effect did not occur in the rats fed a low sodium diet with K supplementation. These results suggest that K supplementation attenuates development of hypertension with reduction of sodium retension in salt-loaded DS rats, which is mediated by the recovery of salt-induced NO production mechanism.

Enhanced Electrical Activity in Mesenteric Arteries From Salt-Loaded Dahl Salt-Sensitive Rats Actions of Prostaglandin H2 on Membrane Channels

Salt loading increases blood pressure in Dahl salt-sensitive (Dahl S) rats. We have previously shown that the mesenteric artery of salt-loaded Dahl S rats exhibits enhanced electrical activity that is corrected by a cycloxygenase inhibitor, indomethacin. Prostaglandin H2 (PGH2) is a product of cycloxygenase that is known as an intrinsic vasoconstricting factor in spontaneously hypertensive rats. Our hypothesis is that tissue production of PGH2 would be involved in the enhanced electrical activity of arteries from salt-loaded Dahl S rats. In the present study, to clarify this possibility, we evaluated the actions of PGH2 on membrane channels in arterial cells from Dahl S rats. Membrane currents were recorded by whole-cell voltage clamp technique in single smooth muscle cells from the mesenteric artery. Application of PGH2 evoked an inward current that was mainly dependent on extracellular Na+ in the physiological extracellular solution. When high Ba2+ solution was used for the extracellular solution, PGH2 also evoked the inward current, suggesting that a divalent cation, such as Ba2+ or Ca2+, could permeate the PGH2-activated channels. In contrast, the L-type Ca2+ channel currents were not enhanced by the application of PGH2. The present results suggest that production of PGH2 contributes to the enhanced electrical activity by activating cation-permeable channels and depolarizing the membrane potential. PGH2 also directly stimulates the Ca2+ influx by activating Ca2+ permeable channels.

Progression of glomerulosclerosis, renal hypertrophy, and an increased expression of fibronectin in the renal cortex associated with aging and salt-induced hypertension in dahl salt-sensitive rats

Aging and hypertension are known to be closely related with the pathogenesis and development of glomerulosclerosis. In this study, we examined the time course changes in the glomerulus associated with salt-induced hypertension using the inbred Dahl salt-sensitive rats. For this purpose, 5-week-old Dahl salt-sensitive rats (n = 36) were fed either 4 % NaCl diet (n = 18) or 0.3 % NaCl diet (n = 18) up to 17 weeks of age. The high salt diet caused a dramatic increase in systolic blood pressure and also a dramatic renal hypertrophy as shown by a significant increase in the kidney weight. Histological examination revealed an age-dependent progression of glomerulosclerosis as documented by a quantitative scoring. This age-dependent progression was further accelerated by the co-existence of salt-induced hypertension in the high salt diet group. Northern blot analysis revealed an increase in the steady state mRNA levels of fibronectin, an important component of mesangial matrices, in the renal cortex, but not in the renal medulla, only in salt-loaded Dahl salt-sensitive rats. These findings indicate that salt-induced hypertension accelerates the age-dependent progression of glomerulosclerosis in Dahl salt-sensitive rats, and fibronectin may play a role in the pathogenesis, development, and progression of glomerulosclerosis associated with salt-induced hypertension.

Enhanced electrical activity in mesenteric arteries from salt-loaded dahl salt-sensitive rats actions of prostaglandin H2 on membrane channels

Salt loading increases blood pressure in Dahl salt-sensitive (Dahl S) rats. We have previously shown that the mesenteric artery of salt-loaded Dahl S rats exhibits enhanced electrical activity that is corrected by a cycloxygenase inhibitor, indomethacin. Prostaglandin H2 (PGH2) is a product of cycloxygenase that is known as an intrinsic vasoconstricting factor in spontaneously hypertensive rats. Our hypothesis is that tissue production of PGH2 would be involved in the enhanced electrical activity of arteries from salt-loaded Dahl S rats. In the present study, to clarify this possibility, we evaluated the actions of PGH2 on membrane channels in arterial cells from Dahl S rats. Membrane currents were recorded by whole-cell voltage clamp technique in single smooth muscle cells from the mesenteric artery. Application of PGH2 evoked an inward current that was mainly dependent on extracellular Nak1 in the physiological extracellular solution. When high Ba2+ solution was used for the extracellular solution, PGH2 also evoked the inward current, suggesting that a divalent cation, such as Ba2+ or Ca2+, could permeate the PGH2-activated channels. In contrast, the L-type Ca2+ channel currents were not enhanced by the application of PGH2. The present results suggest that production of PGH2 contributes to the enhanced electrical activity by activating cation-permeable channels and depolarizing the membrane potential. PGH2 also directly stimulates the Ca2+ influx by activating Ca2+ permeable channels. Am J Hypertens 1997;10:112S–115S © 1997 American Journal of Hypertension, Ltd.

Role of eicosanoids in alteration of membrane electrical properties in isolated mesenteric arteries of salt-loaded, Dahl salt-sensitive rats.

1. The role of eicosanoids in altered membrane electrical properties of Dahl salt-sensitive (DS) rats was investigated, by use of conventional microelectrodes technique, in isolated superior mesenteric arteries of DS rats and Dahl salt-resistant (DR) rats fed either a high or low salt diet. 2. The membrane was significantly depolarized in salt-loaded DS rats compared with the other three groups. In addition, the arteries of salt-loaded DS rats exhibited spontaneous electrical activity. 3. Spontaneous electrical activity in salt-loaded DS rats was inhibited by the following: indomethacin, a cyclo-oxygenase inhibitor; ONO-3708, a prostaglandin H2/thromboxane A2 receptor antagonist; OKY-046, a thromboxane A2 synthase inhibitor; nicardipine, a Ca(2+)-channel antagonist and by Ca(2+)-free solution. In addition, spontaneous electrical activity was enhanced by a thromboxane A2 analogue and by prostaglandin H2. Spontaneous electrical activity was unaffected by phentolamine, atropine and tetrodotoxin. 4. Membrane potential in arteries of salt-loaded DS rats was not affected by either indomethacin or ONO-3708. 5. Spontaneous contraction, sensitive to indomethacin, was present, and contractile sensitivity to high potassium solution was enhanced in arteries of salt-loaded DS rats. 6. These findings suggest that eicosanoid action, together with membrane depolarization, may lead to the activation of voltage-dependent Ca(2+)-channels, thereby causing spontaneous electrical activity in mesenteric arteries of salt-loaded DS rats. In addition, tension data suggest that these changes in membrane properties are related to enhanced contractile activities in salt-loaded DS rats. Mechanisms of depolarization remain to be determined.

Endogenous inhibitor of Na-K-Cl cotransport system in inbred Dahl rats.

Dahl salt-sensitive (DS) rats seem characterized by a ubiquitous increase in Na-K-Cl cotransport activity. Here, an endogenous inhibitor of the Na-K-Cl cotransport system (cotransport inhibitory factor, CIF) was investigated in inbred Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The animals were orally loaded for 10 days with 2% NaCl. Plasma from salt-loaded DS rats inhibited cotransport with a 50% inhibition concentration value (IC50) of 6.4 +/- 0.6% (% plasma concentration, vol/vol) vs. 24.2 +/- 2.2% in DR rats (P < 0.0001). In urine, IC50 for cotransport inhibition was constantly lower in DS before and all during the whole salt-loading period (after 10 days of salt loading, IC50 was 2.59 +/- 0.11% and 6.00 +/- 0.24% in DS and DR rats, respectively; P < 0.0001). After 3 days of salt loading, higher salt appetite in DS rats magnified the differences in urinary CIF excretion. In erythrocytes from DS rats, increased cotransport activity was strongly correlated with urinary CIF excretion (r = 0.967). In conclusion, DS rats present increased plasmatic and urinary CIF levels. This can be a compensatory phenomenon to reduce cotransport hyperactivity and increased NaCl reabsorption at the thick ascending limb of Henle's loop.

P-175 - Beneficial effect of long-term treatment with enalapril on survival rate in high salt-loaded Dahl salt-sensitive rats

P-175 - Beneficial effect of long-term treatment with enalapril on survival rate in high salt-loaded Dahl salt-sensitive rats

AT1 receptor antagonist, TCV 116, does not prevent cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats.

1. We investigated the effects of direct blockade of angiotensin II (AngII) by a potent, non-peptide angiotensin II toff 1 (AT1) receptor antagonist, TCV 116, on the development of cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats. 2. Six week old male Dahl salt-sensitive rats (n = 44) were fed a 4% salt diet and were simultaneously given various doses of TCV 116 orally for 7 weeks. Each control group received vehicle alone. 3. Dietary high salt intake elevated blood pressure continuously and caused left ventricular hypertrophy in rats treated with vehicle. TCV 116 had a minor effect on the rise in blood pressure. Left ventricular mass (left ventricular weight/body-weight) decreased slightly but not significantly, in rats treated with 3 mg/kg per day of TCV 116 (n = 8). Higher doses of TCV 116 (6 and 10 mg/kg per day; n = 8 each) did not show a decrease in left ventricular mass compared with the vehicle control. 4. These results suggest that AngII blockade has only minor effects on hypertension and on cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats and that the renin-angiotensin system may not contribute to the development of cardiac hypertrophy in Dahl salt-sensitive rats on a moderately high-salt diet.

Reduction of development of left ventricular hypertrophy in salt-loaded Dahl salt-sensitive rats by angiotensin II receptor inhibition.

To determine the effect of the angiotensin II AT1 receptor antagonist losartan (DuP753) on echocardiographic left ventricular (LV) anatomy in Dahl rats on high sodium diet, 27 Dahl salt-sensitive (Dahl-S, 13 on drug and 14 receiving tap water) and 27 Dahl salt-resistant rats (Dahl-R, 13 on drug and 14 receiving tap water) were studied by M-mode echocardiography during 8 weeks of 8% NaCl diet. At the endpoint (after 8 weeks or the last echocardiogram for animals who died earlier), Dahl-S receiving losartan had lower LV mass (1.6 +/- 0.4 g/kg 0.59) than Dahl-S receiving tap water (2.2 +/- 0.7 g/kg 0.59; P < .005), although blood pressure was only partially reduced (167 +/- 29 v 195 +/- 52; P = .05). This difference was mainly due to lower LV wall thickness (P < .02), with a less consistent decrease in LV chamber size in Dahl-S receiving losartan. Blood pressure was normal in Dahl-R (tap water group = 116 +/- 11 mm Hg; losartan group = 115 +/- 13 mm Hg) and losartan had no effect on LV mass (1.6 +/- 0.4 g/kg 0.59) in both groups). In the majority of rats, echocardiographic measurements were compared between the end of second or third week and the last available study: LV mass increased in salt-loaded Dahl-S receiving tap water (1.6+/- 0.6 to 2.1 +/- 0.7 g/kg 0.59, P < .04) and was stable in Dahl-S receiving losartan (1.5 +/- 0.1 to 1.5 +/- 0.3 g/kg 0.59), paralleling changes in LV chamber dimension. Thus, a high salt diet leads to hypertension and eccentric LV hypertrophy in Dahl-S but not in Dahl-R. Inhibition of angiotensin II AT1 receptors reduces the development of LV hypertrophy in Dahl-S rats despite lack of efficient control of blood pressure.

Cardiac Hypertrophy and the Blockade of Angiotensin II Receptors by Losartan in Salt-Loaded Dahl Salt-Sensitive Rats.

We studied the effects of direct blockade of angiotensin II by a non-peptide angiotensin II receptor (AT1) antagonist, losartan, on development of cardiovascular hypertrophy in salt-loaded Dahl salt-sensitive (DS) rats. Six-week-old male DS rats were fed a 4% NaCl diet and were simultaneously treated with one of two doses of oral losartan for 7 weeks. Vehicle-treated rats were given tap water alone. Blood pressure and body weight were monitored. The low-dose of losartan (30 mg/kg/day; n=12) blunted the rise in tail-cuff systolic blood pressure only transiently and did not reduce the left ventricular mass (ratio of left ventricular weight/body weight), when compared to the vehicle control (n=12). The high dose of losartan (100mg/kg/day; n=6) blunted the rise in blood pressure; however, left ventricular mass was not significantly lower in rats given the high dose of losartan than in those given vehicle (n= 12). The pressor response to intravenous angiotensin II was greatly suppressed in salt-loaded DS rats treated with 30mg/kg/day of losartan. These results suggest that losartan has minor hypotensive effects without reducing cardiovascular hypertrophy in DS rats fed a 4 % NaCl diet. We conclude that angiotensin II blockade has only minor effects on hypertension and cardiovascular hypertrophy in salt- loaded DS rats, and that the renin-angiotensin system may play no major role in the development of cardiovascular hypertrophy in DS rats on a moderately high-salt diet. (Hypertens Res 1994; 17: 199-203)

Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats

To study the effects of blockade of the renin-angiotensin system upon the development of hypertension, end-organ damage and mortality in Dahl salt-sensitive (DSS) rats using an angiotensin II receptor antagonist, losartan. DSS rats (n = 186) were fed 8% NaCl from 6 to 16 weeks of age. One group received losartan whilst the control group was untreated. Changes in blood pressure and plasma renin activity (PRA), as well as renal and cerebrovascular damage and survival were assessed during the study. Losartan blunted the blood pressure rise only transiently. Salt loading suppressed PRA in both groups until week 4 and thereafter it rose more markedly in the treated group. With no treatment renal lesions were first detected at 2 weeks, and strokes at 6 weeks. However, losartan transiently decreased the incidence and delayed the progression of renal damage and cerebrovascular lesions (strokes) and increased survival. PRA correlated with renal damage and the incidence of strokes in both groups. Blood pressure only partially affected survival, but did not correlate with stroke incidence. These results indicate that whereas the rise in blood pressure is dependent upon sodium loading, morbidity and mortality in salt-loaded DSS rats are associated with activation of the renin-angiotensin system and are only partially related to blood pressure.