Carteolol, a non-conventional partial agonist of β1-adrenoceptors, relaxes phenylephrine-constricted rat aorta through antagonism at α1-adrenoceptors

This in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of β1-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of β1-adrenoceptors or antagonist effect at α1-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD2 = 3.65 ± 0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor NG-nitro-l-arginine methyl ester (100 µM) or cyclo-oxygenase inhibitor indomethacin (10 µM). The effect of carteolol was unaffected by the non-selective β-adrenoceptor antagonist propranolol (1 µM), or the β2-adrenoceptor selective antagonist (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 µM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration–response curves for phenylephrine-induced contraction, exhibiting a pKB of 4.28 ± 0.07. Carteolol affinity for α1-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant α1D-adrenoceptor, the α1-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [3H]prazosin, exhibiting a pKi value (3.39 ± 0.31) similar to its pD2 and not very far from its pKB. In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its α1-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of β-adrenoceptors, particularly of the low-affinity state of β1-adrenoceptors, by the drug.