Dynamic Ca²⁺-Induced Inward Rectification of K⁺ Current During the Ventricular Action Potential

From the Dipartimento di Fisiologia e Biochimica Generali, Università degli Studi di Milano, Milan, Italy.

Correspondence to Dr Antonio Zaza, Dipartimento di Fisiologia e Biochimica Generali, via Celoria 26, I-20133, Milan, Italy. E-mail zanto{at}imiucca.csi.unimi.it

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, Ca²⁺-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_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 Ca²⁺ current by dihydropyridines (DHPs) increased systolic I_Ba and I_0K by 50.7% and 254.5%, respectively. ß-Adrenergic stimulation, when tested on I_0K, 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.

Key Words: inward rectifier K⁺ current • inward rectification • intracellular Ca²⁺ • action potential

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