MINERALOCORTICOID BLOCKADE REDUCES VASCULAR INJURY IN STROKE-PRONE HYPERTENSIVE RATS

Chronic treatment of saline-drinking stroke-prone spontaneously hypert ensive rats (SHRSP) with agents that interfere with the formation or a ctions of angiotensin II (Ang II) prevents the development of stroke a nd renal vascular damage. Ang II, in addition to its direct vascular e ffects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in t hese rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP a t 7.5 weeks of age, Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed m arked proteinuria (150+/-6 mg/d) whereas in spironolactone-treated SHR SP, urinary protein excretion (UPE) averaged 39+/-9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spiron olactone (10 mg/kg/d) and 6 received vehicle. All but one of the contr ol rats displayed signs of stroke and died by 16 weeks of age, while t he spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03), At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247+/-3 mm Hg), yet UPE remained at baseline l evels. In contrast, preterminal UPE averaged 136+/-13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development o f malignant nephrosclerotic and cerebrovascular lesions, These observa tions indicate a vascular and end organ protective effect of spironola ctone in the absence of lowered blood pressure in saline-drinking SHRS P and are consistent with a major role for mineralocorticoids as hormo nal mediators of vascular injury.