Mineralocorticoid and angiotensin receptor antagonism during hyperaldosteronemia

Elevated aldosterone levels induce a spironolactone-inhibitable decrease in cardiac sarcolemmal Na⁺-K⁺ pump function. Because pump inhibition has been shown to contribute to myocyte hypertrophy, restoration of Na⁺-K⁺ pump function may represent a possible mechanism for the cardioprotective action of mineralocorticoid receptor (MR) blockade. The present study examines whether treatment with the angiotensin type 1 receptor antagonist losartan, with either spironolactone or eplerenone, has additive effects on sarcolemmal Na⁺-K⁺ pump activity in hyperaldosteronemia. New Zealand White rabbits were divided into 7 different groups: controls, aldosterone alone, aldosterone plus spironolactone, aldosterone plus eplerenone, aldosterone plus losartan, aldosterone plus losartan and spironolactone, and aldosterone plus losartan and eplerenone. After 7 days, myocytes were isolated by enzymatic digestion. Electrogenic Na⁺-K⁺ pump current (I_p), arising from the 3:2 Na⁺:K⁺ exchange ratio, was measured by the whole-cell patch clamp technique. Elevated aldosterone levels lowered I_p; treatment with losartan reversed aldosterone -induced reduced pump function, as did MR blockade. Coadministration of spironolactone or eplerenone with losartan enhanced the losartan effect on pump function to a level similar to that measured in rabbits given losartan alone in the absence of hyperaldosteronemia. In conclusion, hyperaldosteronemia induces a decrease in I_p at near physiological levels of intracellular Na⁺ concentration. Treatment with losartan reverses this aldosterone-induced decrease in pump function, and coadministration with MR antagonists produces an additive effect on pump function, consistent with a beneficial effect of MR blockade in patients with hypertension and congestive heart failure treated with angiotensin type 1 receptor antagonists.