PREFERENTIAL INHIBITION OF I-KR BY MCI-154, A PUTATIVE CARDIOTONIC CA2-PIG ATRIAL CELLS( SENSITIZER, IN GUINEA)

Objective: To define the electrophysiologic mechanism(s) by which MCI- 154, a putative Ca2+ sensitizer, produces a positive inotropic respons e without a positive chronotropic response, we examined effects of MCI -154 on the action potential of atrial preparations and the membrane c urrents of atrial myocytes. Methods: The action potentias were recorde d from left atrial and sinoatrial node preparations of guinea pigs by the use of standard microelectrode techniques. The whole-cell membrane currents were recorded from enzymatically-dissociated guinea pig atri al myocytes using conventional patch clamp techniques. Results: In iso lated left atria, MCI-154 increased the developed tension in a concent ration-dependent manner. MCI-154 at concentrations of 10 and 100 mu M increased the action potential duration (APD) in left atria stimulated at 0.5 Hz. In sinoatrial node preparations MCI-154 at a concentration of 100 mu M produced a negative chronotropic response and prolonged A PD. In single right atrial myocytes, MCI-154 at concentrations of 10 a nd 100 mu M failed to increase the inward L-type Ca2+ current, but dec reased the delayed rectifier K+ current(I-K) in a concentration-depend ent manner. MCI-154 decreased I-K elicited by short depolarizing pulse s more markedly than that induced by long depolarizing pulses. In addi tion, MCI-154 produced only a little inhibition of I-K in the presence of E-4031, a specific blocker of rapidly activating component of I-K (I-Kr). Conclusions: MCI-154 preferentially blocks I-Kr and the inhibi tory action on I-Kr may be partly involved in the negative chronotropi c and positive inotropic responses in atrial preparations. (C) 1998 El sevier Science B.V. All rights reserved.