Estimation of the nonspecific cardiovascular toxicity of beta-adrenoceptor blocking drugs with different hydrophobic properties in the cat.

The structure-activity relationship between the acute nonspecific cardiovascular depressant effects of the beta-adrenoceptor blocking drugs and their hydrophobic properties was evaluated experimentally for propranolol, pindolol, practolol, and atenolol, in the anaesthetized cat after preceding beta-adrenoceptor blockade. The LD50 values (geometric mean and range in mumol/kg i.v., each drug n = 5) for the nonspecific depression of max dp/dt were: 7.5 (5.6-9.1) for propranolol, 21 (15.5-28) for pindolol, 190 (115-290) for practolol, and 230 (170-400) for atenolol. The respective partition coefficients in octanol buffer (pH 7.0) as a measure of hydrophobicity were: propranolol 5.4, pindolol 0.20, practolol 0.025, and atenolol 0.0032. These experimental data showed a good fit into the regression equation obtained previously [18]. Practolol, in contrast, had a lower toxicity than calculated because of a pronounced intrinsic sympathomimetic activity (ISA), even after catecholamine depletion. The nonspecific cardiovascular toxicity of 15 other clinically used beta-adrenoceptor blocking drugs were estimated from their respective octanol buffer partition coefficients. The fall of the diastolic blood pressure was representative of the toxicity of the compounds. It is concluded that the cardiovascular toxicity is lowest in compounds with low hydrophobicity and with distinct ISA.