uk-66914 and Ventricular-Fibrillation

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)

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Heart; Hemodynamics; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium; Pyrazines; Pyridines; Rabbits; Rats; Rats, Wistar; Ventricular Fibrillation

In a perfused guinea-pig heart model of myocardial ischaemia, reducing coronary flow by 95% for four successive 6 min periods caused a reproducible net loss of K+ into the coronary perfusate. This was reduced in a concentration-dependent manner by ATP dependent K+ channel blockers (glibenclamide and glipizide) and calcium channel blockers (verapamil and nifedipine). Other K+ channel blockers (UK-66,914, 4-aminopyridine, R56865 and phentolamine) and beta 1-adrenoceptor and beta 2-adrenoceptor antagonists (betaxolol and ICI118551) did not reduce this loss significantly. A single 30 min low-flow period reliably induced K+ release and ventricular fibrillation in control hearts. Glibenclamide, glipizide and phentolamine suppressed ventricular fibrillation but not ischaemic K+ loss in this model. R56865 and 4-aminopyridine and coadministration of betaxolol and ICI118551 yielded similar results while UK-66,914 suppressed neither. In our model, modulation of ischemic K+ loss and suppression of ventricular fibrillation were not closely associated and appeared to occur via separate mechanisms.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Benzothiazoles; Calcium Channel Blockers; Disease Models, Animal; Glipizide; Glyburide; Guinea Pigs; In Vitro Techniques; Male; Myocardial Ischemia; Piperidines; Potassium; Potassium Channels; Pyrazines; Pyridines; Sympatholytics; Thiazoles; Ventricular Fibrillation