KATPChannel Opening During Ischemia Effects on Myocardial Noradrenaline Release and Ventricular Arrhythmias

Cardioprotection by KATPchannel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. KATPchannel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of KATPchannel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and Kselective electrodes were inserted in the left ventricular free wall. Cromakalim 3 Mor glibenclamide 3 Mwas added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim n 16 prevented the second rise of extracellular K in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min mean, 169 ± SEM 97 pmolgr dry weight vs. control 941 ± 278 p < 0.05 and 20 min of ischemia 230 ± 125 pmolgr dry wt vs. control 1,460 ± 433 p < 0.05, but after 30 min of ischemia, the difference in noradrenaline release was no longer significant cromakalim 2,703 ± 1,195 pmolgr dry wt vs. control 5,413 ± 1,310 p 0.08. Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts 77 n19, in six of 10 glibenclamidetreated hearts 60 n 15, and in six of 14 cromakalimtreated hearts 43 p NS. Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation mean ± SEM onset after 12.5 ± 1.6 min ischemia vs. control 16.2 ± 0.7 min p < 0.05. Noradrenaline release occurred only in cromakalimtreated hearts with earlyonset arrhythmias whereas no noradrenaline release was observed in cromakalimtreated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the KATPchannel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of KATPopeners during myocardial ischemia.