title: Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice.
abstract: BACKGROUND
  Elevated circulating aldosterone level is associated with impaired cardiovascular function. Although the mechanisms are not fully understood, aldosterone antagonists decrease total and cardiovascular mortality in heart failure and myocardial infarction. Aldosterone induces cardiac fibrosis in experimental models, and it is synthesized locally in rat heart. These observations suggest pathological effects of aldosterone in heart that remain unclear.
  
  
  RESULTS
  Transgenic mice (TG) that overexpress the terminal enzyme of aldosterone biosynthesis, aldosterone synthase (AS), in heart have been raised by gene targeting with the alpha-myosin heavy chain promoter. AS mRNA increased 100-fold and aldosterone concentration 1.7-fold in hearts of male TG mice relative to wild-type. No structural or myocardial alterations were evidenced, because ventricle/body weight, AT1 and AT2 receptor binding, and collagen content were unchanged in TG. No alteration in cardiac function was evidenced by echocardiography, isolated perfused heart, or whole-cell patch clamp experiments. In contrast, coronary function was impaired, because basal coronary flow was decreased in isolated perfused heart (-55% of baseline values), and vasodilatation to acetylcholine, bradykinin, and sodium nitroprusside was decreased by 75%, 60%, and 75%, respectively, in TG mice compared with wild-type, showing that the defect was not related to NO production.
  
  
  CONCLUSIONS
  Increased cardiac aldosterone production in male mice induces a major coronary endothelium-independent dysfunction with no detectable alterations in cardiac structure and function. However, coronary dysfunction may be harmful for coronary adaptation to increased flow demand.
authors.affiliation: INSERM U572, Université Paris 7, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Bendall
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fuchs
authors.forename: Brigitte
authors.initials: B
authors.lastname: Escoubet
authors.forename: Francesca
authors.initials: F
authors.lastname: Rochais
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hoerter
authors.forename: Johnny
authors.initials: J
authors.lastname: Nehme
authors.forename: Marie-Lory
authors.initials: ML
authors.lastname: Ambroisine
authors.forename: Noeleen
authors.initials: N
authors.lastname: De Angelis
authors.forename: Gilles
authors.initials: G
authors.lastname: Morineau
authors.forename: Pauline
authors.initials: P
authors.lastname: d'Estienne
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.forename: Florence
authors.initials: F
authors.lastname: Pinet
authors.forename: Claude
authors.initials: C
authors.lastname: Delcayre
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D007473:Ion Channels / Q000378:metabolism; D017136:Ion Transport; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D009928:Organ Specificity; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011945:Receptors, Angiotensin / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019076:Transgenes; D014664:Vasodilation / Q000187:drug effects
chemical_list: D007473:Ion Channels; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D011993:Recombinant Fusion Proteins; D009599:Nitroprusside; D009569:Nitric Oxide; D000450:Aldosterone; D003094:Collagen; D019405:Cytochrome P-450 CYP11B2; D000109:Acetylcholine; D011188:Potassium; D001920:Bradykinin; D002118:Calcium