The offset of β-adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline

Abstract

1 The aim of the study was to test the hypothesis that the offset of action of β-adrenoceptor antagonists on the heart is related to their lipophilicity, with low and highly lipophilic drugs having a rapid and slow offset, respectively. The effects of β-blockers with low (atenolol), moderate (celiprolol), high (propranolol) and very high (bopindolol) lipophilicity on the contractile responses of the rat right ventricle to isoprenaline were determined.

2 Atenolol at 10⁻⁻⁶ and 10⁻⁻⁵ m, celiprolol at 10⁻⁻⁷, 10⁻⁻⁶ and 10⁻⁻⁵ m, propranolol at 10⁻⁻⁸, 10⁻⁻⁷ and 10⁻⁻⁶ m and bopindolol at 2 × 10⁻⁻⁹ and 10⁻⁻⁸ m caused parallel rightward shifts of the isoprenaline response curves with no effect on maximum responses. The Schild plots for atenolol, celiprolol and propranolol had slopes that were not significantly different from 1, which is indicative of competitive reversible antagonism. The pK_B values were 7.33, 7.78, and 8.79 for atenolol, celiprolol, and propranolol, respectively. The Schild plot for bopindolol had a slope that was significantly greater than 1.

3 Our hypothesis is supported as the effects of propranolol and bopindolol were more slowly offset than those of atenolol and celiprolol. Thus, the concentration-ratio of 141 in the presence of atenolol at 10⁻⁻⁵ m was reduced to 4 after the first wash, whereas the ratio of 100 in the presence of propranolol at 10⁻⁻⁷ m was only reduced to 45 after a similar wash. The ratio of 54 with celiprolol at 10⁻⁻⁶ m was reduced to 5, whereas the ratio of 70 with bopindolol at 10⁻⁻⁸ m was only reduced to 28 by the first wash.

4 The effects of bopindolol were very slowly or not reversible over two washes in the absence or presence of atenolol at 10⁻⁻⁶ m. It is suggested that bopindolol is a very slowly reversible β-blocker, and that this contributes to its slow offset of action.