Mexiletine protects myocardium during acute ischemia by opening sarcolemmal K-ATP channel studies in closed-chest acute ischemia model in rabbits

Objectives: Although we have previously shown that mexiletine might protect myocardium during acute ischemia, the precise mechanism was unclear. In the present study, the mechanism of this effect was examined by using selective K-ATP channel blockers in closed-chest acute ischemia model in rabbits. Methods: In 40 rabbits, the large left ventricular branch (LLVB) of the left coronary artery was occluded for 30 minutes by inserting a catheter bead (psi0.5-0.7 x 1.5 mm) through the left carotid artery and was then reperfused. The rabbits were divided into the following 5 groups: (1) control group (n = 8); (2) mexiletine (Mex) group (n = 8, continuous infusion of Mex 24 mg/kg/h); (3) Mex + 5-hydroxydecanoate (5HD) group (n = 8, preadministration of 5HD, 5 mg/kg, followed by Mex infusion); (4) Mex + HMR1098 (selective sarcolemmal K-ATP channel blocker) group (n = 8, preadministration of HMR1098, 3 mg/kg, followed by Mex infusion); and (5) pilsicainide (Pil) group (n = 8, continuous infusion of Pil 18 mg/kg/h). The incidence of ventricular arrhythmia, hemodynamics, left ventricular ejection fraction (LVEF), and infarction size were evaluated and compared among the 5 groups. Results: The incidence of ventricular arrhythmia was lower in groups treated with Mex than the control. The hemodynamics did not show significant differences among the 5 groups. Although the LVEF at 30 minutes after reperfusion was lower in the Mex group (41 +/- 3%, P < 0.001) than the control group (48 +/- 3%), the LVEF at 360 minutes after reperfusion had recovered and became higher in the Mex group (62 +/- 3%, P < 0.001) than the control group (55 +/- 3%). The infarction size was smaller in the Mex group (30 +/- 5%, P = 0.028) than the control group (51 +/- 8%). These effects of Mex were negated by HMR1098 but not by 5HD and were larger than the effects of Pil. Conclusions: Mex showed improvement in the LVEF in the later phase after reperfusion as well as a reduction in ventricular arrhythmia. The cardioprotective effect of Mex was considered to appear through its action on the sarcolemmal K-ATP channel.