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Electrophysiological analyses of threshold conditions and rate-dependent failure of excitation in single myocytes from rabbit ventricle.

The changes in transmembrane ionic currents that underlie normal excitability and rate-dependent failure were studied in single cells from rabbit ventricle by using whole cell voltage clamp methods. When trains of brief (1 to 2 ms) stimuli are applied at strengths very close to the threshold for excitation, a number of different patterns of action potential entrainment and failure are observed. In an individual cell, a characteristic pattern of entrainment or failure can be maintained for a relatively long time, allowing both a detailed description and a quantitative investigation of the ionic basis for this phenomenon. Three hypotheses for rate-dependent failure of excitation in rabbit ventricle were examined. The first is that following relatively high rates of stimulation, the intracellular calcium ion concentration increases and, secondarily, a background inwardly rectifying potassium ion current (IK1) decreases, thereby lowering the excitation threshold. The second hypothesis is that residual activation of the delayed rectifier potassium ion current (IK) causes the stimulus to become subthreshold as the rate of stimulation increases. The third hypothesis is that small changes in the time and voltage dependence of the inactivation and reactivation of the sodium ion current (INa) result in less net inward ion current for a given waveform of depolarization, and the cell therefore becomes inexcitable (eg, to every second stimulus). The calcium ion hypothesis was tested by buffering changes in intracellular calcium ion concentrations with BAPTA. The results strongly suggest that changes in intracellular calcium ion concentrations do not contribute significantly to the observed patterns of failure of excitation. The delayed rectifier hypothesis was evaluated using the class III antiarrhythmic drug dofetilide, which selectively blocks a large fraction of the IK current in rabbit ventricle. Dofetilide slightly decreased the stimulus threshold, suggesting that residual activation of the rapidly activated outward conductance of potassium ions is an important variable under some conditions. The INa hypothesis was tested by altering the size of INa with tetrodotoxin (TTX). After TTX application, the threshold for excitation increased significantly, and rate-dependent failure and entrainment were no longer observed until the stimulus strength was increased. These results show that INa is an essential variable underlying normal excitation and entrainment in rabbit ventricle. This is plausible because INa is 20 to 50 times larger than either the maximum outward current due to IK1 or the fully activated IK in this tissue.