Comparison of the alpha-adrenoceptor-mediated effects of beta3-adrenoceptor ligands in rat pulmonary artery.

We have recently shown that the beta-adrenoceptor ligands CGP 12177, bupranolol, and SR 59230A (aryloxypropanolamines), but not BRL 37344 and CL 316243 (phenylethanolamines), exhibit significant affinity for alpha1-adrenoceptors and that CGP 12177 displays partial agonist properties at alpha-adrenoceptors in rat pulmonary artery. In this study, bupranolol and SR 59230A were further evaluated for their potential alpha-adrenoceptor mediated effects (i.e., agonist and/or antagonist properties) in rat intralobar pulmonary artery and compared with BRL 37344 and CL 316243. Bupranolol induced a relaxation in phenylephrine-precontracted arteries, but had no effect in prostaglandin F2alpha(PGF2alpha) -precontracted ones. SR 59230A also elicited a relaxation in phenylephrine-precontracted arteries. In PGF2alpha -precontracted arteries, SR 59230A induced a contractile response that was insensitive to the irreversible alpha-adrenoceptor antagonist phenoxybenzamine. BRL 37344 at high concentrations, but not CL 316243, produced slight relaxation in both phenylephrine- and PGF2alpha -precontracted arteries. The contractile response to phenylephrine was antagonized by bupranolol and SR 59230A in a competitive manner (pA2: 6.38 and 7.08 respectively). The concentration-response curve to phenylephrine was also shifted to the right by BRL 37344 (mean pKb: 4.45), but not by CL 316243 (100 microM). This study indicates that the aryloxypropanolamine derivatives bupranolol and SR 59230A exhibit competitive antagonist, but no agonist properties on alpha1-adrenoceptors, SR 59230A also inducing alpha-adrenoceptor-independent contraction. Among the phenylethanolamines, BRL 37344 but not CL 316243, also exerts an antagonist effect on alpha1-adrenoceptors, with a much lower potency than the aryloxypropanolamines studied.