Class III antiarrhythmic action by potassium channel blockade: dofetilide attenuates hypoxia induced electromechanical changes

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Abstract
Objective: The aim was to examine the electromechanical effects of dofetilide, a new class III antiarrhythmic agent, in isolated guinea pig ventricular muscle during hypoxia. Methods: Hypoxia was induced by superfusing guinea pig right ventricular papillary muscles with Tyrode's solution gassed with 95% N2 + 5% CO2 [Po2=5.3(SEM 1.3) kPa]. Prior to hypoxia, the preparations were either pretreated for 30 min with 0.1 μM dofetilide (n=6) or with 100 μM glibenclamide (a blocker of ATP sensitive K+ channels, n=6), or not pretreated (n=6). Sixteen additional preparations were exposed to 1 mM nicorandil (an activator of ATP sensitive K+channels) in the absence (n=6) and presence of dofetilide (n=6) or glibenclamide (n=4). Transmembrane action potentials and developed force were recorded using conventional microelectrode techniques and a force transducer. Results: During normoxia, dofetilide markedly increased APD90 from 236(SEM 6) ms to 298(7) ms (p90 by 47(5)% (p90 by 45(5)% (p90, ERP, and developed force. Conclusions: Dofetilide, like glibenclamide, effectively attenuates hypoxia and nicorandil induced action potential shortening and the associated reduction in contractile force. Thus dofetidile would be expected to retain its antiarrhythmic efficacy during myocardial hypoxia or ischaemia. Cardiovascular Research 1992;26:1109-1115

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