Negative inotropic effects and the hydrophobicity of beta-adrenergic blocking agents

The negative inotropic actions of 12 beta-adrenergic blocking agents, all of which are aryloxyisopropylaminopropanols were studied in isolated left atria from reserpinized guinea-pig hearts. At concentrations between 10 and 1000 microM, all these drugs, with the exception of atenolol, reduced the contractile force by more than 40%. The following order of potency, as measured as ED40, was thus derived:propranolol, alprenolol, D-25, Ko 707, pindolol, oxprenolol, Kö 592, befunolol, metoprolol, Kö 1313, acebutolol and atenolol. On the other hand, the order of the octanol/water partition coefficient (P) was as follows: propranolol, alprenolol, D-25, Kö 707, Kö 592, oxprenolol, befunolol, acebutolol, metoprolol, pindolol, Kö 1313 and atenolol. A significant correlation was found between log l/ED40 and log P. The results indicate that hydrophobicity is a major determinant for the negative inotropic effects of these beta-adrenergic agents.