The relationship between the transient inward current (TI) and other components of slow inward current in mammalian cardiac muscle.

ABSTRACT

When rabbit sino-atrial node preparations and isolated guinea-pig ventricular cells are subjected to Na-K pump blockade (either by reducing external K+ by a factor of 10 sinus node; or by the presence of 10(-7) M ouabain ventricular cells) they develop oscillatory transient inward currents of the kind already recorded in Purkinje fibres and ventricular muscle strands. The time course of these transient currents, generally known as TI's, closely resembles that of the slow component of second inward current (isi,2) previously reported by us as occurring in rabbit sinus node when recorded near its threshold (-40 mV). Moreover, we have found that, under voltage clamp conditions, the 'envelope' of isi currents activated by depolarization from negative membrane potentials matches the outline of the iTI which develops during the initial hyperpolarization. In the sinus node, oscillations of iTI become smaller near O mV but are never flat and there is no clear cut reversal potential, whilst in ventricular cells oscillations and contractions cease at very positive membrane potentials (+35 mV) without the TI current ever becoming net outward. Replacing 75% of the external Na+ with Li+ reduces isi and iTI in the node by about the same proportion strongly suggesting that both are carried by a Na-Ca exchange mechanism. This idea is supported by reproducing the conditions of Na-K pump block in a computer model of the sinus node activity++, when oscillatory currents are generated by variations in activity of the Na-Ca exchange mechanism triggered by fluctuating levels of intracellular calcium. The same model when used to test the hypothesis that isi,2 might be carried by a non-specific ion channel showed that considerable distortion of the action potential would then occur. From the experimental and computed results it is concluded that the majority of isi,2 and iTI currents are both mediated by Na-Ca exchange.