Pharmacological Analysis in Rat of the Role of the ATP-Sensitive Potassium Channel as a Potential Target for Antifibrillatory Intervention in Acute Myocardial Ischaemia

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Abstract
We tested the hypothesis that blockade of the ATP-sensitive K+ channel (IK(ATP)) is an antiarrhythmic mechanism in acute myocardial ischaemia, using an opener of the channel (10μM RP 49356, RP) and a blocker of the channel (10 μM glibenclamide, GL) and a combination of the two drugs (GL + RP, 10 μM each) in a randomised blinded study. Isolated rat hearts (n = 8 per group) were subjected to 30-min left regional ischaemia. GL and GL + RP widened QT interval after 10-min ischaemia (197 ± 39 and 203 ± 20 ms, respectively vs. 154 ± 12 ms in controls), whereas RP significantly shortened QT interval (123 ± 6 ms). GL and GL + RP decreased coronary flow (p < 0.05). RP caused slight increase in flow during ischaemia. These effects are all consistent with modulation of vascular and cardiac IK(ATP). RP alone had no effect on ischaemia-induced arrhythmias. Neither did GL have any effect on the incidence of ventricular fibrillation (VF: 88 vs. 100% in controls). However, GL reduced the incidence of sustained VF (VF lasting continuously for >2 min) to 14% vs. 88% in controls (p < 0.05). Therefore, GL had defibrillatory activity. Surprisingly, in view of these findings, the GL + RP combination significantly reduced the incidence of VF to 25% (from 100% in control hearts, p < 0.05) i.e., had an antifibrillatory effect. So, two agents that produce pharmacological effects attributable to block and opening of IK(ATP) when administered singly had no effects on the incidence of ischaemia-induced VF. The profound and unexpected antiarrhythmic effect observed with the combination of these drugs is best explained by an IK(ATP)-independent pharmacological action of GL, the identity of which remains uncertain. The data do not support the hypothesis that IK(ATP) blockade is a specific antifibrillatory mechanism in acute myocardial ischaemia, although IK(ATP) blockade may represent a defibrillatory mechanism.

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