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

Abstract

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. During 30 min regional ischaemia, 0.3 and 1 μm 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 μm‐treated hearts and 78% in 1.0 μm‐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. QT interval was not affected by UK66,914 in rat (NS), values (mean ± s.e.mean) being 114 ± 8, 121 ± 8, and 113 ± 6 ms in control, 0.3 and 1 μm groups respectively, 10 min after the onset of ischaemia. However, in the rabbit the same concentrations of UK66,914 produced concentration‐dependent widening of QT interval, values being 172 ± 14, 194 ± 9 (NS) and 233 ± 18 ms (P < 0.05), with increasing concentrations of drug, 10 min after the onset of ischaemia. UK66,914 had no substantial effects on haemodynamics (heart rate, coronary flow or recovery of flow during reperfusion), at either concentration, in either species. Occluded zones sizes were similar with increasing concentrations of drug in rat (42 ± 4, 40 ± 2 and 40 ± 2% of total ventricular weight) and rabbit (46 ± 2, 43 ± 2 and 46 ± 3%). Thus, the species‐dependent antiarrhythmic effects of UK66,914 were not attributable to differences in these variables. In conclusion, the rat versus rabbit data indicate that for UK66,914 to inhibit ventricular arrhythmias associated with reperfusion, IK blockade is sufficient and necessary. The rat data indicate that no antiarrhythmic effects occur with the drug during ischaemia when there is no scope for IK blockade. Whilst other mechanisms may be unlikely to be involved, they cannot be excluded completely. Together the rat and rabbit studies indicate that the antiarrhythmic effects of UK66,914 during ischaemia and reperfusion are adequately explained by IK blockade. 1993 British Pharmacological Society