Atypical cardiostimulant β‐adrenoceptor in the rat heart: stereoselective antagonism by bupranolol but lack of effect by some bupranolol analogues

Atypical β‐adrenoceptors resistant to propranolol, but blocked by bupranolol, increase contractile force and/or frequency of the heart in humans and rats. We compared the potencies of the enantiomers of bupranolol and examined the possible effects of seven bupranolol analogues including bevantolol (BEV) at this receptor in pithed and vagotomized rats. CGP 12177, an agonist of the atypical β‐adrenoceptor, increased heart rate dose‐dependently. Its dose–response curve was shifted to the right by S‐(−)‐bupranolol 10 μmol kg−1 by a factor of 8.4, but not affected by the same dose of R‐(+)‐bupranolol. Desmethylbupranolol and compounds BK‐21, BK‐22, BK‐23 and BK‐25 also increased heart rate dose‐dependently. The β1‐adrenoceptor antagonist CGP 20712 given in combination with the β2‐adrenoceptor antagonist ICI 118,551 (0.1 μmol kg−1 each) reduced the positive chronotropic action of the five bupranolol analogues without affecting that of CGP 12177. The potencies of the bupranolol analogues to increase heart rate were correlated (r=0.91, P<0.05) with their affinities for β1‐adrenoceptor binding sites in rat brain cortex membranes labelled with [3H]CGP 12177 (in the presence of ICI 118,551). BK‐26 and BEV, 10 μmol kg−1 each, had only minor effects on heart rate by themselves and did not antagonize the effect of CGP 12177. However, at 1 μmol kg−1, they antagonized the increase in heart rate elicited by the β1‐adrenoceptor agonist prenalterol. In conclusion, bupranolol is a stereoselective antagonist at the atypical cardiostimulant β‐adrenoceptor. The effects of the bupranolol analogues are related to the activation or blockade of β1‐adrenoceptors, but not of atypical β‐adrenoceptors.