EFFECTS OF KT-362, A NEW ANTIARRHYTHMIC AGENT, ON MEMBRANE IONIC CURRENTS OF GUINEA-PIG VENTRICULAR MYOCYTES

We studied the effects of KT-362, (5-[3[2-(3,4-dimethoxyphenyl) -oxopr opyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate), a newly synthe sized vasodilating and antiarrhythmic agent, on membrane currents of s ingle guinea pig ventricular cells, using whole-cell voltage-clamp tec hniques. In the steady state with a stimulation frequency of 0.5 Hz, K T-362 at concentrations of 10 and 30 mu M decreased the peak sodium cu rrent (I-Na) in a concentration-dependent manner, i.e., by 27% end 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 (I-C a) in a concentration-dependent fashion. The delayed rectifier potassi um current and the inward rectifier potassium current were also inhibi ted by KT-362. The effects of KT-362 on I-Na and I-Ca were confirmed i n experiments using ventricular papillary muscle preparations and micr oelectrode techniques. KT-362 (10-300 mu M) decreased the maximum rate of rise of action potentials provoked at normal (2.7 mM) K+ concentra tion and that provoked at high (20 mM) K+ concentration. KT-362 at con centrations over 100 mu M significantly depolarized the resting membra ne, and the action potential duration remained unaltered. From these f indings, 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 suppres ses a variety of membrane ionic currents of cardiac cells. Such multip le inhibitory effects on the myocardium may account for some of the kn own cardioprotective and antiarrhythmic effects of this compound.