Effects of KT-362, a new antiarrhythmic agent, on membrane ionic currents of guinea pig ventricular myocytes.

Abstract

We studied the effects of KT-362, (5-[3[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a newly synthesized vasodilating and antiarrhythmic agent, on membrane currents of single guinea pig ventricular cells, using whole-cell voltage-clamp techniques. In the steady state with a stimulation frequency of 0.5 Hz, KT-362 at concentrations of 10 and 30 microM decreased the peak sodium current (INa) in a concentration-dependent manner, i.e., by 27% and 49%, respectively. The inhibition of INa by this agent was use-dependent: KT-362 (30 microM) inhibited INa by 21% at 0.2 Hz and by 51% at 1 Hz. In addition, KT-362 (10-30 microM) decreased the L-type Ca current (ICa) in a concentration-dependent fashion. The delayed rectifier potassium current and the inward rectifier potassium current were also inhibited by KT-362. The effects of KT-362 on INa and ICa were confirmed in experiments using ventricular papillary muscle preparations and microelectrode techniques. KT-362 (10-300 microM) decreased the maximum rate of rise of action potentials provoked at normal (2.7 mM) K+ concentration and that provoked at high (20 mM) K+ concentration. KT-362 at concentrations over 100 microM significantly depolarized the resting membrane, and the action potential duration remained unaltered. From these findings, we conclude that apart from the alleged inhibitory effects of this agent on the release of calcium from sarcoplasmic reticulum (it is therefore termed "an intracellular Ca++ blocker"), KT-362 suppresses a variety of membrane ionic currents of cardiac cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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@article{Cheng1994EffectsOK, title={Effects of KT-362, a new antiarrhythmic agent, on membrane ionic currents of guinea pig ventricular myocytes.}, author={Yung Neng Cheng and Tatsuto Kiyosue and Makoto Arita}, journal={The Journal of pharmacology and experimental therapeutics}, year={1994}, volume={270 3}, pages={851-7} }