Carvedilol blockade of rat myocardial alpha1-adrenoceptors.
Carvedilol is a combined alpha(1)- and beta-adrenoceptor antagonist. The ability of carvedilol to antagonize functional effects mediated through myocardial alpha(1)-adrenoceptors has never been investigated. We tested the ability of carvedilol to antagonize the inotropic effect mediated by myocardial alpha(1)-adrenoceptors compared to the antagonism of beta-adrenoceptors. Papillary muscles from rat heart left ventricle were mounted in an organ bath and concentration-response experiments for the inotropic effects of separate alpha(1)- and beta-adrenoceptor stimulation were performed in the absence and presence of carvedilol. Carvedilol antagonized myocardial alpha(1)-adrenoceptors with an inhibition constant (K(i)) of 11.0+/-3.0 nmol/l and the functional experiments were supported by radioligand-binding studies. Corresponding functional studies on the response to beta-adrenoceptor stimulation revealed a K(i) of 1.2+/-0.35 nmol/l. Thus, carvedilol antagonizes the myocardial alpha(1)-adrenoceptors with a 9-fold lower potency than the beta-adrenoceptors. Antagonism of myocardial alpha(1)-adrenoceptor evoked effects may contribute to clinical effects of carvedilol.
Qvigstad
Eirik
E
Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. eirik.qvigstad@labmed.uio.no
Osnes
Jan Bjørn
JB
Sandnes
Dagny
D
Schiander
Iwona
I
Bøkenes
Janny
J
Sjaastad
Ivar
I
Skomedal
Tor
T
D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D014316:Tritium
D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D014316:Tritium; D010656:Phenylephrine; D009638:Norepinephrine; D011224:Prazosin