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(Circulation. 2007;116:2435-2443.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Aldosterone-Induced Coronary Dysfunction in Transgenic Mice Involves the Calcium-Activated Potassium (BKCa) Channels of Vascular Smooth Muscle Cells

Marie-Lory Ambroisine, PhD^*; Julie Favre, PhD^*; Patricia Oliviero, BSc; Camille Rodriguez, BSc; Ji Gao, BSc; Christian Thuillez, MD, PhD; Jane-Lise Samuel, MD, PhD; Vincent Richard, PhD; Claude Delcayre, PhD

From Inserm U689 and Paris Diderot University, Paris (M.L.A., P.O., C.R., J.L.S., C.D.), and Inserm U644 and Institute for Biomedical Research, Rouen University Hospital, Rouen (J.F., J.G., C.T., V.R.), France.

Correspondence to Claude Delcayre, PhD, Inserm U689, Cardiovascular Research Center, Inserm Lariboisiere, Hôpital Lariboisière, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, France. E-mail Claude.Delcayre{at}larib.inserm.fr

Received June 15, 2007; accepted September 14, 2007.

Background— Cardiomyocyte-specific overexpression of aldosterone synthase in male (MAS) mice induces a nitric oxide–independent coronary dysfunction. Because calcium-activated potassium (BKCa) channels are essential for vascular smooth muscle cell (VSMC) relaxation, we hypothesized that aldosterone alters their expression and/or function in VSMCs.

Methods and Results— Left coronary artery segments were isolated from MAS or male wild-type mice and mounted in a wire myograph. Responses to acetylcholine were assessed (in the presence of a nitric oxide synthase inhibitor) without or with the cyclooxygenase inhibitor diclofenac, the KCa inhibitors charybdotoxin plus apamin, or the BKCa inhibitor iberiotoxin. Expression of BKCa was quantified in hearts by real-time quantitative polymerase chain reaction and Western blot and in isolated coronary arteries by polymerase chain reaction. The effect of aldosterone on BKCa expression also was studied in cultured rat aortic VSMCs. Acetylcholine-mediated coronary relaxation was markedly decreased in MAS mice and was prevented by spironolactone. Diclofenac did not affect the MAS-induced impairment in the responses to acetylcholine, whereas charybdotoxin plus apamin virtually abolished the relaxation in both male wild-type and MAS mice. After iberiotoxin, relaxation to acetylcholine was decreased to a larger extent in male wild-type than in MAS, leading to similar levels of relaxation. BKCa- and -β1 subunit expressions were significantly decreased in MAS heart and coronary arteries. In cultured VSMCs, aldosterone induced a concentration-dependent decrease in BKCa expression, which was prevented by spironolactone.

Conclusions— Aldosterone overexpression altered VSMC BKCa expression and coronary BKCa-dependent relaxation. The resulting alteration of relaxing responses may contribute to the deleterious effects of aldosterone in cardiovascular diseases. BKCa channels may therefore be useful therapeutic targets in cardiovascular diseases.

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