Effects of the bradycardic agent ZD 7288 on membrane voltage and pacemaker current in sheep cardiac Purkinje fibres.

Abstract

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 mumol/l and to 5% of control at 10 mumol/l. The threshold potential of i(f)-activation was unaffected at a concentration of 1 mumol/l ZD 7288. The time constant of i(f)-activation at different test potentials was not changed by 1 mumol/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 mumol/l. There was strong correlation over the concentration range of 0.01 to 10 mumol/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 -100 mV. The correlation coefficient was r = 0.97. These results will explain the decrease in frequency of spontaneously active (about 0.6 Hz) Purkinje fibres.(ABSTRACT TRUNCATED AT 250 WORDS)