Abstract-Chronic treatment of saline-drmkmg stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angotensm II (Ang II) prevents the development of stroke and renal vascular damage Ang II, m addltlon to its direct vascular effects, stimulates the synthesis and release of aldosteroneTo assess the role of aldosterone m the development of pathologc changes m these rats, we implanted time-release pellets containing 200 mg of the mmeralocortlcold receptor antagomst, spu-onolactone, mto 14 SHRSP at 7 5 weeks of age Eight SHRSP httermates received placebo pellets Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) (PRA) and aldosterone as independent nsk factors for heart attack and stroke ' They found that among the patients who developed strokes and myocardlal mfarctlons, all had normal or high PRA, and aldosterone secretlon Previous studies by our group and others have provided expenmental evidence to support a role for the renm-angotensm-aldosterone system (RAAS) m the development of vascular qury, as angotensm converting enzyme (ACE) mhlbltors2-6 and Ang II receptor antagonlsts7-9 prevented the development of stroke and malignant nephrosclerosls m SHRSP Since these studies were conducted m salt-loaded SHRSP, which respond to these agents with nummal blood pressure lowermg, they provided evidence for a pathophyslolog& role for Ang II m the development of vascular lesions of malignant nephrosclerosls independent of severely elevated blood pressure Consistent with a role for Ang II was the finding that SHRSP display a paradoxical increase m PRA with rime, despite continued salt-loading 3 9,'" Although Ang II stimulates the synthesis and release of aldosterone," " m addmon to its direct vascular actions, a role for mmeralocortlcolds m the pathology of SHRSP

Abstract-Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (nϭ8); captopril alone (50 mg ⅐ kg; or captopril and aldosterone at 20 (nϭ6) or. Systolic blood pressure was markedly elevated in all groups. Vehicle-and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21Ϯ3% and 29Ϯ3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 g ⅐ kg Ϫ1 ⅐ d Ϫ1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16Ϯ3% and 21Ϯ2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure. Key Words: hypertension Ⅲ kidney Ⅲ malignant nephrosclerosis Ⅲ captopril Ⅲ aldosterone T he participation of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertensive vascular injury has been widely demonstrated. 1 Numerous studies with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin (Ang) II receptor antagonists have clearly identified Ang II as a major factor responsible for the development of end-organ damage in hypertensive vascular disease. However, mineralocorticoids may also play an important role, because animals with deoxycorticosterone acetate (DOCA)-salt hypertension typically develop severe vascular pathology, and resultant malignant nephrosclerosis, myocardial necrosis, and stroke, 2-5 despite low levels of plasma renin activity. 2,5,6 The renal lesions that develop in DOCA-salt hypertensive rats are characterized by fibrinoid necrosis of blood vessels and proliferative arteriopathy 2-4 and are very similar to those seen in stroke-prone spontaneously hypertensive rats (SHRSP) receiving a high sodium chloride diet 7-11 and in rats with Ang II-salt-induced hypertension. 12 We have shown that chronic administration of agents that inter...

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To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and Nomega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.

These findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis.

Clearance and micropuncture studies were conducted on 6-wk-old spontaneously hypertensive rats (SHR) of the Okamoto-Aoki strain and normotensive Wistar-Kyoto rats (WKY) under euvolemic conditions. Mean arterial pressure in SHR was elevated by 18 mmHg and their kidneys were vasoconstricted with reduced blood flow; resistances in preglomerular vessels and efferent arterioles were elevated 2.8 and 2 times, respectively, above WKY values. Whole kidney glomerular filtration rate (GFR) and single nephron glomerular filtration rate (SNGFR), based on fluid collection from either proximal or distal convolutions, were 25-30% lower in SHR. Fractional reabsorptions of fluid load by the proximal convoluted tubule (43%) and by the loop of Henle (52-55%) were similar in both groups. Accordingly, SHR exhibited less fluid delivery from the proximal convolution (8 vs. 12 nl/min) and to the distal convolution (3 vs. 5 nl/min). Glomerular dynamics in hypertensive and normotensive strains were characterized by filtration pressure disequilibrium. Estimated glomerular capillary pressure and mean effective ultrafiltration pressure were similar in SHR and WKY. SHR had a lower glomerular ultrafiltration coefficient than WKY (0.011 vs. 0.016 nl X s-1 X mmHg-1), which, combined with a lower glomerular plasma flow (41 vs. 73 nl/min), quantitatively accounted for the lower SNGFR in 6-wk-old SHR. These findings document important differences in renal function in young SHR compared with WKY that may participate in the development of hypertension.

The renin-angiotensin-aldosterone system plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur, whereby aldosterone levels return to or exceed baseline levels. The classic effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, blood pressure reduction or fluid loss could not account for the results of the Randomized Aldactone Evaluation Study, which showed that a low dose of spironolactone in addition to conventional therapy could decrease the overall risk of mortality by 30% among patients with severe congestive heart failure. The action of aldosterone at nonepithelial sites in the brain, heart, and vasculature is consistent with the presence of mineralocorticoid receptors in these tissues. Aldosterone has a number of deleterious effects on the cardiovascular system, including myocardial necrosis and fibrosis, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release, and production of cardiac arrhythmias. Several studies have now shown vascular and target-organ protective effects of aldosterone receptor antagonism in the absence of significant blood pressure lowering, consistent with a major role for endogenous mineralocorticoids as mediators of cardiovascular injury. The advent of selective aldosterone receptor antagonists such as eplerenone should prove of great therapeutic value in the prevention of cardiovascular disease and associated end-organ damage.

The influence of chronic treatment with the angiotensin I converting enzyme (ACE) inhibitor enalapril on blood pressure, kidney function, and survival was examined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed a Japanese rat chow plus a 1% NaCl drinking solution beginning at 7-8 weeks of age developed severe hypertension and stroke; 14 of 18 untreated control SHRSP died by 14 weeks of age and exhibited evidence of cerebrovascular lesions. When enalapril (15 mg/kg/day) was included in the drinking solution of 15 SHRSP, blood pressure was initially reduced by only a slight degree, whereas survival unproved markedly; only one of 10 SHRSP died before the rest were killed at 18 to 21 weeks. The remaining five enalapril-treated SHRSP lived beyond 36 weeks and on histological examination exhibited no evidence of cerebrovascular lesions. Chronic enalapril treatment also prevented the greater urinary excretion of protein and severe renal lesions observed in untreated SHRSP but did not affect urinary salt and water excretion. In anesthetized rats, glomerular filtration rate and tubular reabsorption of water were lower hi untreated control SHRSP when compared with enalapril-treated SHRSP. Mean arterial pressure was comparable in both groups. These data support a possible role for ACE inhibition in the prevention of stroke and maintenance of kidney function independent of any marked change in blood pressure of SHRSP. Whether the protective effects of ACE inhibition relate to reduced angiotensin H formation, increased tissue kinins, or another mechanism remains to be determined. {Hyper-tension 1989;13:115-121) I n 1974 Okamoto and coworkers 1 reported the development of a stroke-prone substrain of the spontaneously hypertensive rat (SHRSP). These animals developed severe hypertension and a high incidence (80%) of cerebrovascular hemorrhage or infarction after 15 weeks of age. The pial arteries of SHRSP showed cellular hyperplasia or proliferation of adventitial cells and fibrinoid necrosis, 1 which resulted in microinfarction. 2 Parenchymal brain lesions were noted that were thought to be the result of vascular leakage.34 Similar abnormalities were observed in the microvasculature of the heart, kidney, and other organs. SHRSP From the Departments of Pharmacology, Pathology, and Medicine, New York Medical College, Valhalla, New York.Portions of this work were previously published in abstract form (FedProc 1987 ;46:1290).Supported by Grant HL-35522 (to C.T.S.) from the National Institutes of Health, Bethesda, Maryland.Address for reprints: Charles T. Stier Jr., PhD, Department of Pharmacology, Basic Science Building, New York Medical College, Valhalla, NY 10595.Received February 5, 1988; accepted October 14, 1988. fed a Japanese rat chow exhibited a higher incidence of stroke than SHRSP fed an American rat chow (88% vs. 30% by 9 months of age). 5 Elevation of sodium intake (by replacing normal drinking water with a 1% NaCl solution) also increased blood pressure and accelerated the onset ...