Mexiletine Protects Myocardium During Acute Ischemia by Opening Sarcolemmal K-ATP Channel

Cardioprotective Effects of Sarcolemmal and Mitochondrial K-ATP Channel Openers in an Experimental Model of Autoimmune Myocarditis

“…In contrast, we previously documented the cardioprotective effect of Mex in an acute ischemia model. 4) Although Mex has sodium channel blocking effects as well as sarcolemmal K-ATP channel opening effects, we concluded that the cardioprotective effect of Mex depended on the sarcolemmal K-ATP channel opening effect because its cardioprotective effect was totally suppressed by HMR-1098, the selective sarcolemmal K-ATP channel blocker used in the study. 4) The time span of the myocardial injury in acute myocarditis is basically different from acute ischemia, in other words, the former appears in days or weeks, but the latter appears in minutes or hours.…”

“…4) Although Mex has sodium channel blocking effects as well as sarcolemmal K-ATP channel opening effects, we concluded that the cardioprotective effect of Mex depended on the sarcolemmal K-ATP channel opening effect because its cardioprotective effect was totally suppressed by HMR-1098, the selective sarcolemmal K-ATP channel blocker used in the study. 4) The time span of the myocardial injury in acute myocarditis is basically different from acute ischemia, in other words, the former appears in days or weeks, but the latter appears in minutes or hours. However, from the point of view of the process of the appearance of the final ventricular dysfunction, they are similar to each other because myocardial injury in the earlier phase results in ventricular dysfunction in the later phase in both diseases.…”

“…This result indicates that shortening the myocardial action potential duration in the acute phase of myocardial injury may result in later myocardial protection possibly through the reduction in the intracellular calcium overload. 4,20,21) In contrast, Nic affected neither the myocarditis nor MAPD in the acute phase, but the Nic treatment resulted in better ventricular function in the chronic phase. Because the redox state of the mitochondria improved in the EAM+Nic groups in comparison with the control EAM group, protection of the mitochondrial function during the acute phase seemed to be the mechanism of the cardioprotection by Nic, similar to the acute ischemia model.…”

“…The area infiltrated by inflammatory cells and/or fibrosis was evaluated using Mac SCOPE software (Mitani Co., Japan) and was expressed as the percentage of the whole ventricular area. 4,13) Evaluation of mitochondrial function: In randomly selected rats, the contents of the metabolites in the ventricular myocardium were enzymatically measured to evaluate the mitochondrial function on day 21 or day 60 as summarized in Table II. Since Mex, a sarcolemmal K-ATP channel opener, rarely affects mitochondrial function, it was not assessed in the rats treated with Mex.…”

“…This response is considered to be an auto-cardioprotective effect during ischemic conditions, which is known to be enhanced by sarcolemmal K-ATP channel openers. [3][4][5][6][7] However, K-ATP channels are found not only in the sarcolemma of myocytes, but also in the mitochondrial membrane, and openers of these mitochondrial K-ATP channels, such as nicorandil, have been proven to play an important role in its cardioprotective effect by protecting mitochondrial function, especially in short-term acute ischemia. [8][9][10] It has been reported that an increase in ventricular wall stress causes prolongation of the action potential duration, particularly in damaged myocardium with heart failure.…”