BOPINDOLOL - A SLOWLY DISSOCIATING ANTAGONIST FROM THE BETA-ADRENACEPTORS IN GUINEA-PIG ATRIA

The dissociating and/or residual inhibitory effects of bopindolol from beta-adrenoceptors of atria strips pretreated with this drug which wa s then washed out with buffers on the responses to isoprenaline were d etermined and compared with those of propranolol, pindolol, atenolol, and the two active metabolites of bopindolol: 18-502 and 20-785. Low c oncentrations of bopindolol (10(-9) to 10(-8) mol/l) and the active me tabolite 18-502 (10(-9) mol/l) produced rightward shifts of the concen tration-response curves. On the other hand, high concentrations of bop indolol (10(-7) mol/l) and metabolite 18-502 (10(-8) and 10(-7) mol/l) produced a reduced maximum response by isoprenaline, suggesting that these nonparallel rightward shifts have pD(2) values of 7.57 (bopindol ol) and 7.67 (18-502), respectively, at 0 min after washout with buffe rs. Pindolol (10(-7) mol/l) and propranolol (10(-7) and 10(-8) mol/l) also produced a rightward shift of isoprenaline response curves, and t hese concentration-response curves in guinea pig atria strips pretreat ed with pindolol (10(-7) mol/l) and propranolol (10(-6) mol/l) recover ed to control levels. Neither of these drugs, however, reduced the max imum response by isoprenaline. A high concentration (10(-5) mol/l) of atenolol was required for a rightward shift of the isoprenaline concen tration-response curve, and this drug also did not reduce the maximum response. Thus, we conclude that bopindolol and metabolite 18-502 slow ly dissociate and act as noncompetitive beta-antagonists rather than e asily reversible beta-adrenoceptor antagonists.