American Heart Association, Circulation Research, 9(82), p. 947-956, 1998
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Abstract —Inward rectification, an important determinant of cell excitability, can result from channel blockade by intracellular cations, including Ca 2+ . However, mostly on the basis of indirect arguments, Ca 2+ -mediated rectification of inward rectifier K + current ( I K1 ) is claimed to play no role in the mammalian heart. The present study investigates Ca 2+ -mediated I K1 rectification during the mammalian ventricular action potential. Guinea pig ventricular myocytes were patch-clamped in the whole-cell configuration. The action potential waveform was recorded and then applied to reproduce normal excitation under voltage-clamp conditions. Subtraction currents obtained during blockade of K + currents by either 1 mmol/L Ba 2+ ( I Ba ) or K + -free solution ( I 0K ) were used to estimate I K1 . Similar time courses were observed for I Ba and I 0K ; both currents were strongly reduced during depolarization (inward rectification). Blockade of L-type Ca 2+ current by dihydropyridines (DHPs) increased systolic I Ba and I 0K by 50.7% and 254.5%, respectively. β-Adrenergic stimulation, when tested on I 0K , had an opposite effect; ie, it reduced this current by 66.5%. Ryanodine, an inhibitor of sarcoplasmic Ca 2+ release, increased systolic I Ba by 47.7%, with effects similar to those of DHPs. Intracellular Ca 2+ buffering (BAPTA-AM) increased systolic I Ba by 87.7% and blunted the effect of DHPs. Thus, I K1 may be significantly reduced by physiological Ca 2+ transients determined by both Ca 2+ influx and release. Although Ca 2+ -induced effects may represent only a small fraction of total I K1 rectification, they are large enough to affect excitability and repolarization. They may also contribute to facilitation of early afterdepolarizations by conditions increasing Ca 2+ influx.