Carteolol, a non-conventional partial agonist of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through antagonism at alpha(1)-adrenoceptors.
This in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of beta(1)-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of beta(1)-adrenoceptors or antagonist effect at alpha(1)-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD(2)=3.65+/-0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (100 microM) or cyclo-oxygenase inhibitor indomethacin (10 microM). The effect of carteolol was unaffected by the non-selective beta-adrenoceptor antagonist propranolol (1 microM), or the beta(2)-adrenoceptor selective antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 microM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration-response curves for phenylephrine-induced contraction, exhibiting a pK(B) of 4.28+/-0.07. Carteolol affinity for alpha(1)-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant alpha(1D)-adrenoceptor, the alpha(1)-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [(3)H]prazosin, exhibiting a pK(i) value (3.39+/-0.31) similar to its pD(2) and not very far from its pK(B). In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its alpha(1)-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of beta-adrenoceptors, particularly of the low-affinity state of beta(1)-adrenoceptors, by the drug.
Floreani
Maura
M
Department of Pharmacology and Anaesthesiology, University of Padova, Italy. m.floreani@unipd.it
Quintieri
Luigi
L
Varani
Katia
K
Dorigo
Maria Teresa
MT
Dorigo
Paola
P
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D002354:Carteolol / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D002354:Carteolol; D015237:Dinoprost; C049763:CGP 20712A; D011224:Prazosin