The renin-angiotensin-aldosterone system in experimental mineralocorticoid-salt-induced cardiac fibrosis

Aldosterone infused for 8 wk to uninephrectomized rats drinking saline solution causes cardiac fibrosis. To investigate the renin-angiotensin system (RAS) in this process, we blocked angiotensin-converting enzyme with perindopril and angiotensin I receptors with losartan. To distinguish aldosterone effects via 11β-hydroxysteroid dehydrogenase type 2-protected epithelial mineralocorticoid receptors (MR) and unprotected cardiac MR, we compared preferential exclusion of aldosterone from unprotected MR by corticosterone and generalized MR blockade by K¹ canrenoate. Perindopril and losartan modestly lowered blood pressure (BP); neither affected cardiac hypertrophy, hydroxyproline content, or perivascular fibrosis, and both slightly attenuated aldosterone effects on interstitial collagen. Corticosterone did not affect cardiac hypertrophy but halved aldosterone- induced elevation of BP and collagen levels. Canrenoate halved the increase in BP and hypertrophy and completely reversed aldosterone-induced increase in cardiac collagen. We conclude that 1) the circulating and tissue RAS are, at most, minor contributors to cardiac fibrosis in aldosterone-infused, salt- loaded rats; and 2) both BP elevation and increased cardiac collagen appear to reflect aldosterone occupancy of unprotected MR, consistent with a direct cardiac effect of aldosterone on fibrosis.