Abstract
Despite efforts to elucidate its pathophysiology, ischemia–reperfusion injury lacks an effective preventative intervention. Because transient receptor potential cation channel subfamily M member 4 (TRPM4) is functionally expressed by many cell types in the cardiovascular system and is involved in the pathogenesis of various cardiovascular diseases, we decided to assess its suitability as a target of therapy. Thus, the aim of this study was to examine the possible cardioprotective effect of 9-phenanthrol, a specific inhibitor of TRPM4. Isolated Langendorff-perfused rat hearts were pretreated with Krebs–Henseleit (K–H) solution (control), 9-phenanthrol, or 5-hydroxydecanoate (5-HD, a blocker of the ATP-sensitive potassium channel) and then subjected to global ischemia followed by reperfusion with the K–H solution. To evaluate the extent of heart damage, lactate dehydrogenase (LDH) activity in the effluent solution was measured, and the size of infarcted area of the heart was measured by 2,3,5-triphenyltetrazolium chloride staining. In controls, cardiac contractility decreased, and LDH activity and the infarcted area size increased. In contrast, in hearts pretreated with 9-phenanthrol, contractile function recovered dramatically, and the infarcted area size significantly decreased. The cardioprotective effects of 9-phenanthrol was not completely blocked by 5-HD. These findings show that 9-phenanthrol exerts a cardioprotective effect against ischemia in the isolated rat heart and suggest that its mechanism of action is largely independent of ATP-sensitive potassium channels.
Highlights
Despite significant advances in therapeutic techniques, ischemic heart disease remains the leading cause of mortality and heart failure in most countries [1]
Early reperfusion can salvage the myocardium after ischemia, reperfusion induces myocardial injury called ‘‘reperfusion injury,’’ which attenuates the benefits of primary percutaneous coronary intervention and thrombolytic therapy [2]
After 30 min of global ischemia, left ventricular developed pressure (LVDP) in the I/R (n = 6) and DMSO (n = 6) groups recovered by only 1366% and 1768%, respectively, at the end of the 3 h period of reperfusion
Summary
Despite significant advances in therapeutic techniques, ischemic heart disease remains the leading cause of mortality and heart failure in most countries [1]. TRPM4 is activated following receptor mediated calcium mobilization and represents a regulatory mechanism that controls the magnitude of calcium influx by modulating the membrane potential and the driving force for calcium entry through other calcium-permeable pathways [8]. This channel is widely expressed and is abundant in the heart tissue. The most specific inhibitor of TRPM4 channels currently available is 9-phenanthrol [11,12], which abolishes arrhythmias induced by hypoxia and reoxygenation in the mouse ventricle [13] Despite these reports, the physiological and pathological role of TRPM4 in heart function is poorly understood
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