Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts.

1. UK66,914 is a specific and selective blocker of the delayed rectifying potassium current (IK). The effectiveness of IK block as a mechanism for prevention of ischaemia- and reperfusion-induced arrhythmias was tested by use of UK66,914: its actions in rat, a species deficient in cardiac IK were compared with its actions in rabbit, a species possessing functional cardiac IK. Antiarrhythmic actions in rabbit but none in rat is the only outcome possible if selective IK blockade is responsible for the antiarrhythmic actions of the drug during ischaemia and/or reperfusion. 2. During 30 min regional ischaemia, 0.3 and 1 microM UK66,914 had no influence on the incidence of ventricular fibrillation (VF) in rat (n = 9/group), values being 78% in controls, 100% in 0.3 microM-treated hearts and 78% in 1.0 microM-treated hearts (NS). UK66,914 also had no effect on reperfusion-induced VF incidence (100% in each group), nor on the latency to onset of ischaemia- or reperfusion-induced arrhythmias. In contrast, in rabbit (n = 13/group), similar concentrations of drug reduced the incidence of reperfusion-induced VF from 77% in controls, to 38% and 31% (P < 0.05) respectively. The incidence of ischaemia-induced arrhythmias was too low in controls to permit detection of an antiarrhythmic effect in rabbit; however no drug-induced proarrhythmia was seen.(ABSTRACT TRUNCATED AT 250 WORDS)