Electromechanical effects of zatebradine on isolated guinea pig cardiac preparations

The effects of zatebradine on rate and contractile force and transmembrane action potentials were studied in isolated guinea pig atria and ventricular papillary muscles. In spontaneously beating right atria, zatebradine, 10(-7)-10(-4) M, produced a negative chronotropic effect (IC50 = 6.5 +/- 3.0 x 10(-6) M) and prolonged the recovery of the sinus function. In addition, it produced a biphasic effect on the atrial contractility, so that at concentrations up to 10(-5) M, it exerted a positive inotropic effect, whereas at higher concentrations, a negative inotropic effect was observed (IC50 = 9.0 +/- 0.3 x 10(-5) M). In electrically driven left atria, zatebradine produced a negative inotropic effect, though no changes were observed in the total contraction time or the time to peak tension. In papillary muscles, zatebradine > or = 5 x 10(-6) M caused a significant decrease in the maximum upstroke velocity (Vmax) without altering the resting membrane potential and exerted biphasic effects on the action potential duration (APD). At concentrations up to 5 x 10(-5) M, it prolonged the APD, whereas at higher concentrations, it shortened the APD. In addition, zatebradine, 10(-4) M, significantly reduced the amplitude and Vmax of the slow action potentials elicited by isoproterenol in K(+)-depolarized papillary fibres. In the presence of zatebradine, trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (frequency-dependent Vmax block), which was augmented at higher rates of stimulation. The time constant for the recovery of Vmax from the frequency-dependent block was 2.9 s.(ABSTRACT TRUNCATED AT 250 WORDS)