Carvedilol blockade of alpha1- and beta-adrenoceptor induced inotropic responses in rats with congestive heart failure.
Carvedilol is a combined alpha(1)- and beta-adrenoceptor antagonist. We investigated the ability of carvedilol to antagonize functional effects mediated through myocardial alpha(1)-adrenoceptors in failing vs. non-failing (sham-operated) control hearts and compared such antagonisms to those of myocardial beta-adrenoceptors. Congestive heart failure was induced in Wistar rats by coronary artery ligation. Papillary muscles experiments were performed. Carvedilol antagonized inotropic effects mediated through myocardial alpha(1)-adrenoceptors with similar potencies in failing (pK(i)=7.7 (95%, CI; 7.4-8.0)) and sham-operated hearts (pK(i)=7.9 (95%, CI; 7.6-8.1)). The potency for the alpha(1)-adrenoceptors was 10-30-fold lower than that for the beta-adrenoceptors. In failing hearts, the alpha(1)-adrenoceptor mediated response was similar in size to the attenuated beta-adrenoceptor mediated inotropic response. The beta-adrenoceptor mediated lusitropic effects were not, however, attenuated in failing compared to sham-operated hearts. A low degree of alpha(1)-adrenoceptor blockade in the myocardium may contribute to the beneficial effects of carvedilol in heart failure.
Qvigstad
Eirik
E
Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. eirik.qvigstad@labmed.uio.no
Sjaastad
Ivar
I
Bøkenes
Janny
J
Schiander
Iwona
I
Solberg
Line
L
Sejersted
Ole M
OM
Osnes
Jan-Bjørn
JB
Skomedal
Tor
T
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000150:complications; D009638:Norepinephrine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000077261:Carvedilol; D010656:Phenylephrine; D007545:Isoproterenol; D009638:Norepinephrine