Both Mitochondrial KATP Channel Opening and Sarcolemmal KATP Channel Blockage Confer Protection Against Ischemia/Reperfusion-Induced Arrhythmia in Anesthetized Male Rats

Abstract

Aim: This study was performed to assess the effect of selective sarcolemmal adenosine triphosphate (ATP)-sensitive K⁺ channel (K_ATP) inhibition and the mitochondrial K_ATP channel activation on ischemia and reperfusion (I/R)-induced arrhythmias in different gender of rats. We compared the effect of a selective sarcolemmal K_ATP channel blocker HMR 1098, a selective mitochondrial K_ATP channel opener diazoxide, a nonselective K_ATP channel opener pinacidil, and the combination of pinacidil with HMR 1098 on the incidence and duration of ventricular arrhythmias in 2 groups: anesthetized males (n = 31) and females (n = 31). Main Methods: Ischemia and reperfusion was produced by occluding the left main coronary artery of Sprague-Dowley rats for 6 minutes followed by re-opening of the artery for 6 minutes. Key Findings: The arrhythmia score and the duration of arrhythmias were significantly reduced by HMR 1098, diazoxide, and pinacidil in male rats. The combination of the pinacidil with HMR 1098 did not change the antiarrhythmic effect of pinacidil. The duration of arrhythmas was shorter in females than that in the corresponding males. Drug treatments were not effective in decreasing arrhythmias in female groups to the same extent as in the male group. However, the mitochondrial K_ATP channel activation that is provided by the combination of pinacidil with HMR 1098 significantly decreased the total length of arrhythmias in females. Significance: Results of the current study indicate that both mitochondrial K_ATP channel activation and sarcolemmal K_ATP channel inhibition exert antiarrhythmic action in male rats. The antiarrhythmic effect of pinacidil is not depend on the sarcolemmal K_ATP channel opening. These results also indicate that K_ATP channel modulators show no discernable effect in female rats due to the already low incidence of arrhythmias in females.

Keywords

HMR 1098 diazoxide pinacidil KATP channel ischemia reperfusion arrhythmia

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