9-Phenanthrol, a TRPM4 Inhibitor, Protects Isolated Rat Hearts from Ischemia–Reperfusion Injury

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.

Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression

“…Clusterin, also known as testosterone-repressed message-2, is overexpressed in the rat prostate during castration-induced programmed cell death [20]. As clusterin is usually present in resistant cells [21,22], it has been described as an anti-apoptotic factor.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Of note, in a second study, no difference in infarcted area was noted between wild-type and TRPM2-knockout mice and, surprisingly, the knockout animals even showed worse cardiac function after injury. The TRPM4 inhibitor 9-phenanthrol also protected rat hearts from ischemia/ reperfusion damage (Wang et al, 2013b).…”

The TRPM4 channel inhibitor 9‐phenanthrol

“…In this model, it was hypothesized that EADs were formed in the conductive tissue such as Purkinje fibres, where TRPM4 channels are highly expressed (Liu et al ., ), and were transmitted to the ventricular cells. In a second study, the cardioprotective effect of 9‐phenanthrol was tested in a rat isolated whole heart perfused using a Langendorff apparatus (Wang et al ., ). Ischaemia‐reperfusion was mimicked by switching off and on the perfusion of physiological solution in the coronary vessels.…”