(+/-)-Pindolol acts as a partial agonist at atypical beta-adrenoceptors in the guinea pig duodenum

Abstract

The agonistic and antagonistic effects of (+/-)-pindolol (1-(1H-indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol) were estimated to clarify whether (+/-)-pindolol acts as a partial agonist on atypical beta-adrenoceptors in the guinea pig duodenum. (+/-)-Pindolol induced concentration-dependent relaxation with a pD2 value of 5.10 +/- 0.03 and an intrinsic activity of 0.83 +/- 0.03. However, the relaxations to (+/-)-pindolol were not antagonized by the non-selective beta1- and beta2-adrenoceptor antagonist (+/-)-propranolol (1 microM). In the presence of (+/-)-propranolol (1 microM), the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol (30 microM) induced a rightward shift of the concentration-response curves for (+/-)-pindolol (apparent pA2 = 5.41 +/- 0.06). In the presence of (+/-)-propranolol, (+/-)-pindolol (10 microM) weakly but significantly antagonized the relaxant effects to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl) amino]propyl]phenoxyacetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A([4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride). These results demonstrate that (+/-)-pindolol possesses both agonistic and antagonistic effects on atypical beta-adrenoceptors in the guinea pig duodenum.