Ketamine attenuates the Na + -dependent Ca 2+ overload in rabbit ventricular myocytes in vitro by inhibiting late Na + and L-type Ca 2+ currents

Abstract

Aim:Intracellular Ca 2+ ([Ca 2+ ] i) overload occurs in myocardial ischemia. An increase in the late sodium current (I NaL) causes intracellular Na + overload and subsequently [Ca 2+ ] i overload via the reverse-mode sodium-calcium exchanger (NCX). Thus, inhibition of INaL is a potential therapeutic target for cardiac diseases associated with [Ca 2+ ] i overload. The aim of this study was to investigate the effects of ketamine on Na + -dependent Ca 2+ overload in ventricular myocytes in vitro.Methods:Ventricular myocytes were enzymatically isolated from hearts of rabbits. I NaL, NCX current (I NCX) and L-type Ca 2+ current (I CaL) were recorded using whole-cell patch-clamp technique. Myocyte shortening and [Ca 2+ ] i transients were measured simultaneously using a video-based edge detection and dual excitation fluorescence photomultiplier system.Results:Ketamine (20, 40, 80 μmol/L) inhibited I NaL in a concentration-dependent manner. In the presence of sea anemone toxin II (ATX, 30 nmol/L), I NaL was augmented by more than 3-fold, while ketamine concentration-dependently suppressed the ATX-augmented I NaL. Ketamine (40 μmol/L) also significantly suppressed hypoxia or H 2 O 2 -induced enhancement of I NaL. Furthermore, ketamine concentration-dependently attenuated ATX-induced enhancement of reverse-mode I NCX. In addition, ketamine (40 μmol/L) inhibited I CaL by 33.4%. In the presence of ATX (3 nmol/L), the rate and amplitude of cell shortening and relaxation, the diastolic [Ca 2+ ] i, and the rate and amplitude of [Ca 2+ ] i rise and decay were significantly increased, which were reverted to control levels by tetrodotoxin (TTX, 2 μmol/L) or by ketamine (40 μmol/L).Conclusion:Ketamine protects isolated rabbit ventricular myocytes against [Ca 2+ ] i overload by inhibiting I NaL and I CaL.