Potassium channel blocker dofetilide does not abolish ischaemic preconditioning

Abstract

Ischaemic preconditioning (IP) is a powerful mechanism for infarct reduction. Enhanced K⁺ conductance and shortening of action potential duration in the early phase of the sustained ischaemic episode have been proposed as important factors in the IP mechanism for infarct reduction. We have investigated whether the potassium channel-blocking class III anti-arrhythmic agent dofetilide could abolish IP in an in situ rabbit heart infarct model. Dofetilide is a specific blocker of the delayed rectifier potassium channel and thus lengthens the action potential duration by reducing potassium conductance during repolarization.

Anaesthetized, open-chest rabbits were subjected to 30 min of regional ischaemia and 180 min of reperfusion. The ischaemic risk zone was determined by fluorescent particles, and infarct size was determined by TTC staining. Three groups were investigated: control, ischaemic preconditioned (IP) and IP plus dofetilide-treated (IPdof). The preconditioning protocol was 5 min regional ischaemia and 10 min reperfusion. The IPdof group underwent the same preconditioning protocol but additionally received dofetilide 20 ug kg⁻¹ i.v. during the first 2 min of the first reperfusion period. Compared to pre-drug values dofetilide increased monophasic action potential duration from 149.2±11.5ms (n=4) to 215.8±12.4 ms, supporting blockade of the delayed rectifier potassium channel. At the same time heart rate was decreased from 255.5±12.5 to 230.3±8.2. The results expressed as percent infarction of the risk zone+SEM for the different groups were as follows: control (n=ll), 42.4+7.1; IP (n=6), 7.6±4.3*; IPdof (n=7), 12.3±4.1* (*p≤ 0.05 vs. control). These results show that the potassium channel-blocking agent dofetilide given after the preconditioning ischaemia but before the sustained ischaemia does not abolish ischaemic preconditioning.

Key Words:

• heart
• infarct size
• monophasic action potentials
• rabbit