Isoproterenol Antagonizes Prolongation of Refractory Period by the Class III Antiarrhythmic Agent E-4031 in Guinea Pig Myocytes Mechanism of Action

Sanguinetti, Michael C.
Jurkiewicz, Nancy K.
Scott, Ann
Siegl, Peter K.S.

From Merck Sharp & Dohme Research Laboratories, Department of Pharmacology, West Point, Pa.

Address for correspondence: Michael C. Sanguinetti, Merck Sharp & Dohme Research Laboratories, Department of Pharmacology, WP26-265, West Point, PA 19486.

Previously published as a preliminary report (Biophys J 1990;57:142a).

Received March 28, 1990; accepted August 15, 1990.

Circulation Research 68(1):p 77-84, January 1991.

The mechanism by which isoproterenol (ISO) prevents the prolongation of action potential duration (APD) and refractory period (RP) by the class III antiarrhythmic agent E-4031 was studied. E-4031 (1 μM) increased RP by 501% with no effect on contractile force in papillary muscles isolated from guinea pig heart. ISO (1 μM) increased force of contraction more than fivefold and decreased RP by 25%. The prolongation of RP by E-4031 was prevented by pretreatment of muscles with ISO. The prolongation of APD in isolated guinea pig ventricular myocytes by 5 1 μM E-4031 also was antagonized by prior exposure of the cells to 1 μM ISO. Instantaneous currents and delayed rectifier K⁺ currents, I_K, were measured in isolated myocytes using the suction microelectrode voltage-clamp technique. Currents were measured in response to 225 -msec depolarizing pulses from a holding potential of -40 mV. Previous studies have demonstrated that I_K in these cells results from activation of two distinct outward K⁺ currents, I_Ks and I_Kr (specifically blocked by E-4031). ISO doubled the magnitude of IKS without significant effect on I_Kr. The instantaneous current, putatively identified as a Cl⁻ current, also was doubled by ISO but was unaffected by E-4031. The augmented conductance of IKS and instantaneous current by ISO results in a decrease in RP. The small effect of E-4031 on APD and RP in the presence of ISO results from the smaller contribution of I_Kr relative to the augmented repolarizing currents.