K-ATP channel opening during ischemia: Effects on myocardial noradrenalinerelease and ventricular arrhythmias

Cardioprotection by K-ATP channel openers during ischemia is well documente d although ill understood. Proarrhythmic effects may be an important drawba ck. K-ATP channel modulation influences neurotransmitter release during isc hemia in brain synaptosomes. Therefore, we studied the effects of K-ATP cha nnel modulation on myocardial noradrenaline release and arrhythmias in isch emic rabbit hearts. Isolated rabbit hearts were perfused according to Lange ndorff and stimulated. Local electrograms were recorded and K+-selective el ectrodes were inserted in the left ventricular free wall. Cromakalim (3 muM or glibenclamide (3 muM) was added 20 min prior to induction of global isc hemia. After 15, 20, or 30 min of ischemia. hearts were reperfused and nora drenaline content of the first 100 ml of reperfusate was measured. Cromakal im (n = 16) prevented the second rise of extracellular [K+] in accordance w ith its cardioprotective effect. Cromakalim significantly reduced noradrena line release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. cont rol 941 +/- 278, p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr 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 <plus/minus> 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.0 8). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 1 3 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fi brillation (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 cromakalim- treated hearts with early-onset arrhythmias whereas no noradrenaline releas e was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K-ATP channel by cromakalim during ischemia reduces myocardial noradrenaline release and pos tpones the onset of irreversible damage, contributing to the cardioprotecti ve potential of K-ATP openers during myocardial ischemia.