CLASS-III ANTIARRHYTHMIC ACTION BY POTASSIUM CHANNEL BLOCKADE - DOFETILIDE ATTENUATES HYPOXIA INDUCED ELECTROMECHANICAL CHANGES

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 muM dofetilide (n=6) or with 100 muM 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 (p<0.05) and the effective refractory period (ERP) from 248(5) ms to 315(6) ms (p<0.05). In the drug free group, 60 min hypoxia decreased APD90 by 47(5)% (p<0.05), ERP by 48(4)% (p<0.05) and developed force by 71(6)% (p<0.05) of baseline, respectively. These hypoxia induced effects were significantly attenuated after pretreatment with dofetilide or glibenclamide. Nicorandil decreased APD90 by 45(5)% (p<0.05), ERP by 44(6)% (p<0.05), and developed force by 69(10)% (p<0.05) of baseline, respectively. Pretreatment with dofetilide or glibenclamide also significantly attenuated the nicorandil induced decreases in APD90, 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.