Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice.
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.
Garnier
Anne
A
INSERM U572, Université Paris 7, France.
Bendall
Jennifer K
JK
Fuchs
Sebastien
S
Escoubet
Brigitte
B
Rochais
Francesca
F
Hoerter
Jacqueline
J
Nehme
Johnny
J
Ambroisine
Marie-Lory
ML
De Angelis
Noeleen
N
Morineau
Gilles
G
d'Estienne
Pauline
P
Fischmeister
Rodolphe
R
Heymes
Christophe
C
Pinet
Florence
F
Delcayre
Claude
C
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
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