EFFECTS OF THE BRADYCARDIAC AGENT ZD-7288 ON MEMBRANE VOLTAGE AND PACEMAKER CURRENT IN SHEEP CARDIAC PURKINJE-FIBERS

The bradycardic mechanism of ZD 7288 (4-(N-ethyl-N-phenylamino) -1,2-dimethyl-6-(methylamino)pyrimidinium chloride) was investigated in sheep cardiac Purkinje fibres. The pacemaker i(f)-current measured with the two-microelectrode voltage-clamp technique, as well as the diastolic depolarization rate and the frequency of spontaneously active fibres were evaluated. ZD 7288 did inhibit i(f)-current. The i(f)-amplitude recorded with a 0.8s-lasting test pulse from about - 50 mV to - 100 mV was reduced to 50% of control at 0.85 mu mol/l and to 5% of control at 10 mu mol/l. The threshold potential of i(f)-activation was unaffected at a concentration of 1 mu mol/l ZD 7288. The time constant of i(f)-activation at different test potentials was not changed by 1 mu mol/l ZD 7288. The drug was equally effective during i(f)-activation with a 0.5 s-lasting test pulse applied at 0.05 Hz or 0.5 Hz, During long lasting (5 s) hyperpolarizing test pulses (-120 mV) the inhibition of i(f)-current was removed. In constantly stimulated Purkinje fibres (0.5 Hz) the slope of the early diastolic depolarization was decreased by ZD 7288, The half-maximal effect occurred at 0.92 mu mol/l. There was strong correlation over the concentration range of 0.01 to 10 mu mol/l ZD 7288 between the decrease of the slope of early diastolic depolarization and inhibition of i(f)-amplitude recorded with 0.8s-lasting test pulses to -100mV. The correlation coefficient was r = 0.97. These results will explain the decrease in frequency of spontaneously active (about 0.6 Hz) Purkinje fibres. At 0.3 mu mol/l ZD 7288 spontaneous activity had stopped in 8 of 11 preparations. Complete recovery of drug-induced effects on the frequency was gained after 3 h of wash-out with drug-free solution.