Dynamic Ca2+-induced inward rectification of K+ current during the ventricular action potential

Abstract

Inward rectification, an important determinant of cell excitability, can result from channel blockade by intracellular cations, including Ca2+. However, mostly on the basis of indirect arguments, C2+-mediated rectification of inward rectifier K+ current (I(K1)) is claimed to play no role in the mammalian heart. The present study investigates Ca2+-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 Ba2+ (I(Ba)) or K+-free solution (I(OK)) were used to estimate I(K1). Similar time courses were observed for I(Ba) and I(OK); both currents were strongly reduced during depolarization (inward rectification). Blockade of L-type Ca2+ current by dihydropyridines (DHPs) increased systolic I(Ba) and I(OK) by 50.7% and 254.5%, respectively. β-Adrenergic stimulation, when tested on I(OK), had an opposite effect; ie, it reduced this current by 66.5%. Ryanodine, an inhibitor of sarcoplasmic Ca2+ release, increased systolic I(Ba) by 47.7%, with effects similar to those of DHPs. Intracellular Ca2+ 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 Ca2+ transients determined by both Ca2+ influx and release. Although Ca2+-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 Ca2+ influx.