Effects of JTV-519, a novel anti-ischaemic drug, on the delayed rectifier K+ current in guinea-pig ventricular myocytes

We studied the effects of a newly synthesized anti-ischaemic agent, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2. 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) on the delayed rectifier potassium current (IK). using guinea-pig ventricular myocytes and whole-cell voltage-clamp techniques, under blockade of the L-type calcium current (I-Ca,I-L) by D600 (1 mu M) or nitrendipine (5 mu M). The I-K in guinea-pig ventricular cells consists of two different components; the rapidly activating, E4031-sensitive component (I-Kr) and the slowly activating E4031-nsistant component (I-Ks). Under steady-state conditions, JTV-519 (1 and 5 mu M) did not change the amplitude of I-Ks remaining after blockade of I-Kr with 5 mu M E4031. The effect of JTV-519 on I-Kr was assessed using short (50 ms) pulses which evoked a tail current that was sensitive to E4031 but not to chromanol 293B, a specific blocker of I-Ks. JTV-519 suppressed the I-Kr with a half-maximal inhibitory concentration of 1.2 mu M. Selective inhibition of I-Kr by this agent was confirmed by using the "envelope of tails" test. These results suggest that the blockade of I-Kr may underlie the prolongation of action potential duration in ventricular muscle and QT-intervals alleged to occur in animal as well as human hearts.