摘要：This study used radioligand binding assay methods and pharmacological experiments to examine whether bopindolol, possessing a long-lasting action in addition to potent β-adrenoceptor antagonistic effects, is a slowly dissociating antagonist. In addition, the slow dissociation of two of its metabolites, 18-502 (4-(3-tert-butylamino-2-hydroxypropoxy)-2-methyl indole) and 20-785 (4-(3-tert-butylaminopropoxy)-2-carboxyl indole), which have potent β-blocking activities, was also assessed. The blockade of 3H-CGP12177 binding sites in rat heart and brain induced by pindolol was readily reversed by washing, whereas this inhibition by bopindolol and 18-502 was not easily reversed by washing. In addition, specific bindings of the hearts of the treatment animals with 20-785, atenolol, (±) propranolol, nadolol and celiprolol and of washout were 86.7, 78.8, 77.5, 82.3 and 79.9% of the control, respectively. These blockades by the treatment of each drug and washout in the brain were, however, lower than those in the hearts. On the other hand, when the left and right atria were pretreated with propranolol, bopindolol and 18-502, the inotropic and chronotropic actions of isoprenaline were inhibited by these drugs even though they were not present in the extracellular medium. Pretreatment with 20-785, atenolol and nadolol was readily reversed for both inotropic action and chronotropic rate, and inhibition by celiprolol and pindolol remained at 25% of the control at 240 min after treatment with these drugs. A good correlation between inhibitory binding percentage in the hearts and inhibitory inotropic or chronotropic actions were observed, although it was not observed in the brain. Thus, these results suggest that bopindolol and 18-502 are slowly dissociating β-adrenoceptor antagonists and this property may explain its long-lasting anti-hypertensive effects when compared to other β-blockers.
