title: Isoproterenol antagonizes prolongation of refractory period by the class III antiarrhythmic agent E-4031 in guinea pig myocytes. Mechanism of action.
abstract: 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 microM) increased RP by 50% with no effect on contractile force in papillary muscles isolated from guinea pig heart. ISO (1 microM) 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 microM E-4031 also was antagonized by prior exposure of the cells to 1 microM ISO. Instantaneous currents and delayed rectifier K+ currents, IK, 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 IK in these cells results from activation of two distinct outward K+ currents, IKs and IKr (specifically blocked by E-4031). ISO doubled the magnitude of IKs without significant effect on IKr. 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 IKr relative to the augmented repolarizing currents.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Department of Pharmacology, West Point, Pa 19486.
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: N K
authors.initials: NK
authors.lastname: Jurkiewicz
authors.forename: A
authors.initials: A
authors.lastname: Scott
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002469:Cell Separation; D004553:Electric Conductivity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology; D010210:Papillary Muscles / Q000187:drug effects; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D007545:Isoproterenol