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 (n=8);
captopril alone (50 mg. kg-1. d-1, orally) (n=10);
aldosterone infusion alone (40 microg. kg-1. d-1, SC) (n=7); or
captopril and
aldosterone at 20 (n=6) or 40 (n=7) microg. kg-1. d-1. Systolic blood pressure was markedly elevated in all groups. Vehicle- and
aldosterone-infused SHRSP developed severe
proteinuria and comparable degrees of renal injury (21+/-3% and 29+/-3%, 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 microg. kg-1. d-1 in
captopril-treated SHRSP resulted in the development of severe renal lesions (16+/-3% and 21+/-2%, 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.