REOXYGENATION-INDUCED ARRHYTHMOGENIC TRANSIENT INWARD CURRENTS IN ISOLATED CELLS OF THE GUINEA-PIG HEART

Transient inward currents (I(ti)), activated by a rise in intracellular Ca concentration, are believed to trigger cardiac arrhythmias in reperfused hearts. In this report, I(ti) in isolated cardiocytes from the guinea-pig were evoked by reoxygenation following a period of anoxia of between 4 min and 35 min. Reoxygenation was performed 1 min after the full development of an anoxia-induced time-dependent K current. This current disappeared within 2 - 6 s and in the following 10 s I(ti) developed to maximum amplitude. I(ti) were evoked using a constant pulse pattern (holding potential V(h) = -45 mV; test potential V(t) = + 10 mV; pulse duration 350 ms; frequency 1 Hz). In more than 95% of the cells, I(ti) at the holding potential I(ti) (-45 mV) declined with a time constant of tau = 670 +/- 240 ms (mean +/- SD, n = 17). In two cells, undamped oscillatory currents were observed. The amplitude of I(ti) (-45 mV) was proportional to the amplitude and duration of the preceding depolarizing test pulse. Test pulses of long duration (500 ms and 1000 ms, mean +/- SD) to potentials positive to +10 mV produced slowly decaying tail currents (tau = 391 +/- 51 ms, mean +/- SD), which superimposed with I(ti) (-45 mV). The current/voltage relationship of I(ti) peaked between - 30 mV and - 10 mV and approximated zero at the most positive potentials, i.e. no reversal of I(ti) was found up to + 80 mV. Using double-pulse protocols (prepulse potential + 40 mV), I(ti) were enhanced at potentials negative to - 30 mV and were also present in the range of the normal resting potential of ventricular heart cells. The instantaneous current-voltage relationship was monotone between - 50 mV and + 40 mV. Because of the dependence of I(ti) on the preceding depolarization, the instantaneous current-voltage relationship provides more reliable information on the voltage dependence of I(ti). The interval between two subsequent I(ti) (- 45 mV) values was 237 +/- 35 ms (mean +/- SD, n = 27) and depended on the amplitude of I(ti) (- 45 mV) to increase by 5.2 +/- 0.5% (mean +/- SD) per 100 pA decrease in I(ti) (- 45 mV). A simple noise analysis showed that if one assumes that ionic channels are responsible for the generation of I(ti) (- 45 mV), their unitary conductance cannot exceed 0.36 pS. We conclude that reoxygenation-induced I(ti) are triggered by a cyclic release of Ca from the sarcoplasmic reticulum and provide evidence that they are mediated by the electrogenic Na/Ca exchanger. The arrhythmogenic potency of reoxygenation-induced I(ti) is demonstrated under current-clamp conditions.