Effects of KT-362, a new antiarrhythmic agent, on membrane ionic currents of guinea pig ventricular myocytes
Cheng, Y.N.; Kiyosue, T.; Arita, M.
Journal of Pharmacology and Experimental Therapeutics 270(3): 851-857
1994
ISSN/ISBN: 0022-3565 PMID: 7932196 Document Number: 437433
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 mu-M decreased the peak sodium current (I-Na) in a concentration-dependent manner, i.e., by 27% and 49%, respectively. The inhibition of I-Na by this agent was use-dependent: KT-362 (30 mu-M) inhibited I-Na. by 21% at 0.2 Hz and by 51% at 1 Hz. In addition, KT-362 (10-30 mu-M) decreased the L-type Ca current (1c.) 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 I-Na and I-Ca were confirmed in experiments using ventricular papillary muscle preparations and microelectrode techniques. KT-362 (10-300 mu-M) 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 mu-M 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. Such multiple inhibitory effects on the myocardium may account for some of the known cardioprotective and antiarrhythmic effects of this compound.