Comparison Of L-Celiprolol And D-Celiprolol In Ganglionic-Blocked Dogs

The present study examined effects of the stereoisomers of celiprolol and further examined cardiostimulatory effects of celiprolol. In the anesthetized, ganglionicblocked dog, both I- and d-celiprolol, 3 mg/kg, i.v., showed cardioselective beta adrenoceptor antagonist activity, although blockade of isoproterenol-induced increases in heart rate and contractile force with I-celiprolol was more effective. The two stereoisomers had equivalent cardiostimulatory effects, increasing heart rate by 24 ± 7 and 18 ± 3 beats/min and right ventricular contractile force by 37 ± 11 and 24 ± 11%, respectively (all P < 0.05). After propanolol, 1 mg/kg + 0.3 mg/kg/hr, the cardiostimulatory effect of d-celiprolol was abolished, whereas that of i-celiprolol was unchanged. Dose-response curves for heart rate and contractile force stimulation by d- and I-celiprolol were parallel with I-celiprolol being approximately 100 times more potent than d-celiprolol and 3 times more potent than racemic celiprolol. These observations suggested that the physiologic effects of celiprolol may be largely mediated via I-stereoisomer. In additional experiments cardiostimulatory effects of racemic celiprolol, 30 μg/kg, were inhibited by propranolol. Dose-response curves for celiprolol alone and in the presence of propranolol were parallel. Beta-blockade shifted the effects 1.5 log units to the right and affected chronotropic and inotropic activities similarly. Biochemical studies of celiprolol showed no significant inhibition of canine kidney sodium potassium ATPase, or of multiple forms of canine cardiac cyclic nucleotide phosphodiesterase. In conclusion, both I- and d-celiprolol are cardioselective beta-blocking agents with I-celiprolol being the more potent stereoisomer. Also, the propranolol insensitive cardiac stimulatory activity of celiprolol may illustrate a complex interaction between beta antagonist with and withous ISA rather than a novel positive inotropic mechanism.