title: Aldosterone-induced coronary dysfunction in transgenic mice involves the calcium-activated potassium (BKCa) channels of vascular smooth muscle cells.
abstract: 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.
  
  
  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-alpha and -beta1 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.
authors.affiliation: Inserm U689 and Paris Diderot University, Paris, France.
authors.forename: Marie-Lory
authors.initials: ML
authors.lastname: Ambroisine
authors.forename: Julie
authors.initials: J
authors.lastname: Favre
authors.forename: Patricia
authors.initials: P
authors.lastname: Oliviero
authors.forename: Camille
authors.initials: C
authors.lastname: Rodriguez
authors.forename: Ji
authors.initials: J
authors.lastname: Gao
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
mesh_terms: D000450:Aldosterone / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology
chemical_list: D024681:Potassium Channels, Calcium-Activated; D000450:Aldosterone