PARTIAL AGONIST ACTIVITY OF CELIPROLOL

Celiprolol given intravenously (i.v.) to pithed rats in the dose range of 0.1-10,000 mug/g produced a dose-dependent increase in heart rate (HR) which was greatest (123 beats/min) at 1,000-3,000 mug/kg. This partial agonist effect was blocked by the selective beta1-adrenoceptor antagonist CGP 20712A. Celiprolol also produced a vasodepressor effect in this dose range which was abolished by the relatively selective beta2-adrenoceptor antagonist ICI 118551 but not CGP 20712A. The magnitude of this intrinsic sympathomimetic activity (ISA) response was not significantly altered by reserpine pretreatment. Celiprolol also antagonised the effects of isoprenaline 0.05 mug/kg on HR and blood pressure (BP). The beta1 selectivity of celiprolol as an antagonist in pithed rats (beta1/beta2 = 340:1) was similar to that observed in studies with isolated guinea pig atria and trachea (beta1/beta2 = 63:1), both being considerably greater than that observed with atenolol. Celiprolol, however, like atenolol, potentiated the bronchoconstrictor responses to histamine (3 mug/kg). Metabolic studies of rats and human urine failed to show significant amounts of potentially vasoactive metabolites. These data are consistent with celiprolol acting as both a beta1- and beta2-adrenoceptor partial agonist.