An analysis of the rate-dependent action of lidoflazine in mammalian sino-atrial node and Purkinje fibres.

Lidoflazine is an anti-anginal drug whose beneficial effect is to reduce the heart rate increment on exercise. Micro-electrode recording was performed in the spontaneously-beating, isolated guinea-pig sino-atrial node. It was shown that low concentrations (less than 5 X 10(-6) M) of lidoflazine alone did not alter action potential configuration or beating frequency. However, the drug reduced the spontaneous rate and the slope of the diastolic depolarization in the presence of catecholamine. This effect of lidoflazine was more pronounced at higher catecholamine concentrations. The action of lidoflazine on the hyperpolarization-activated current if was studied using a 2-micro-electrode voltage-clamp technique on shortened sheep Purkinje fibres. The activation curve for if was not affected by the drug. The slope of the fully-activated current-voltage relation was reduced by a mean of 20.1% on exposure to 5 X 10(-6) M lidoflazine. Using a computer model of Purkinje fibre action potentials, the observed reduction in maximal if conductance was shown to account quantitatively for the effects of lidoflazine. It is proposed that lidoflazine slows the heart by reducing the conductance of the if channel. This may be brought about by a fall in intracellular calcium concentration.