Inhibition of catecholamine-induced cardiac fibrosis by an aldosterone antagonist.
In heart failure, the renin-angiotensin-aldosterone and the sympathetic systems are overactivated and lead to formation of cardiac fibrosis, which contributes to the aggravation of cardiac function. The aim of the present study was to evaluate the role of aldosterone and angiotensin II on formation of left ventricular fibrosis induced by chronic beta-adrenergic stimulation with isoproterenol (iso) in the rat heart failure model induced by myocardial infarction (MI). Rats were submitted to chronic treatment with either the aldosterone receptor antagonist potassium canrenoate (pc, 20 mg/kg/d) or both aldosterone and angiotensin II receptor antagonists with addition of losartan (los, 10 mg/kg/d). Isoproterenol induced cardiac hypertrophy, which was completely inhibited by potassium canrenoate alone in atria and by potassium canrenoate plus losartan in infarcted ventricles. Isoproterenol also induced cardiac fibrosis, which was completely inhibited in infarcted rats by potassium canrenoate alone in right and left ventricles. In left ventricle, extent of fibrosis was, for control MI, 1.30 +/- 0.34%; MI + iso, 2.50 +/- 0.27%; MI + iso + pc, 0.82 +/- 0.11%; and MI + iso + pc + los, 1.47 +/- 0.31%. The deleterious effects of beta-adrenoceptor stimulation on cardiac fibrosis seem therefore to involve aldosterone action. These results suggest a transregulation between the adrenergic and mineralocorticoid pathways, most likely at the nucleus level, with activation of profibrotic genes.
Bos
Romain
R
Service de Pharmacologie, CHU Pitié Salpêtrière, Paris, France.
Mougenot
Nathalie
N
Findji
Laurent
L
Médiani
Odile
O
Vanhoutte
Paul M
PM
Lechat
Philippe
P
D000318:Adrenergic beta-Agonists; D000450:Aldosterone / Q000502:physiology; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002191:Canrenoic Acid / Q000494:pharmacology*; D005355:Fibrosis / Q000139:chemically induced / Q000517:prevention & control; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007545:Isoproterenol; D019808:Losartan / Q000494:pharmacology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000150:complications; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology
D000318:Adrenergic beta-Agonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000451:Mineralocorticoid Receptor Antagonists; D011943:Receptors, Adrenergic, beta; D000804:Angiotensin II; D000450:Aldosterone; D002191:Canrenoic Acid; D019808:Losartan; D007545:Isoproterenol