title: Mineralocorticoid and angiotensin receptor antagonism during hyperaldosteronemia.
abstract: 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.
authors.affiliation: Department of Cardiology, Royal North Shore Hospital, St. Leonards, Sydney, Australia. amihaili@doh.health.nsw.gov.au
authors.forename: Anastasia S
authors.initials: AS
authors.lastname: Mihailidou
authors.forename: Mahidi
authors.initials: M
authors.lastname: Mardini
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Matthew
authors.initials: M
authors.lastname: Raison
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077545:Eplerenone; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006929:Hyperaldosteronism / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008274:Magnesium / Q000097:blood; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000097:blood; D011817:Rabbits; D012964:Sodium / Q000097:blood; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D057911:Angiotensin Receptor Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D019808:Losartan; D011188:Potassium