K-ATP channel modulation in working rat hearts with coronary occlusion: Effects of cromakalim, cicletanine, and glibenclamide

Objectives: We studied the effects of ATP-sensitive potassium channel (K-ATP) modulation on ischemic cardiac performance and reperfusion-induced ventricular fibrillation (VF), and assessed the contribution of K-ATP to the cardioprotective and anti-arrhythmic effect of the anti-hypertensive drug cicletanine. Methods: Isolated working rat hearts, subjected to a 10-min coronary occlusion followed by reperfusion, were perfused in the presence of vehicle, 0.1-60 mu M cromakalim, an opener of K-ATP; 3-60 mu M cicletanine; and 0.1-10 mu M glibenclamide, a blocker of K-ATP, respectively. Results: All concentrations of cicletanine, similarly to 0.1-10 mu M cromakalim, attenuated ischemia-induced deterioration of aortic flow, left ventricular developed pressure, and left ventricular end-diastolic pressure. In contrast to cromakalim, cicletanine did not increase coronary flow. Cicletanine (60 mu M) and cromakalim (10 and 60 mu M) significantly reduced the incidence of reperfusion-induced VF; however, 60 mu M cromakalim triggered VF during ischemia. Lower concentrations of cromakalim and cicletanine did not produce an anti-arrhythmic effect. Cardiac functional parameters were concentration dependently worsened by glibenclamide, and the drug did not change the incidence of VF. Glibenclamide (0.1 mu M) did not significantly affect cardiac performance, but it did abolish the anti-ischemic effect of cromakalim (1-10 mu M) and cicletanine (60 mu M). Glibenclamide suppressed the anti-arrhythmic effect of 10 and 60 mu M cromakalim; however, it did not affect the anti-arrhythmic effect of cicletanine. Conclusions: (i) The anti-ischemic but not the anti-arrhythmic effect of cicletanine may involve opening of K-ATP, (ii) opening of K-ATP attenuates, inhibition of the channel exacerbates functional consequences of coronary occlusion, and (iii) K-ATP opening attenuates reperfusion-induced VF, but it triggers ischemia-induced VF. K-ATP blocking does not affect VF.