9-Phenanthrol, a TRPM4 inhibitor, protects isolated rat hearts from ischemia-reperfusion injury.
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.
Department of Cardiology, Graduate School, Dalian Medical University, Dalian, China.
Jing
J
Wang
Ken
K
Takahashi
Hulin
H
Piao
Peng
P
Qu
Keiji
K
Naruse
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010616:Phenanthrenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014325:Tromethamine
D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D054086:KATP Channels; C074097:Krebs-Henseleit solution; D010616:Phenanthrenes; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat; D014325:Tromethamine; C052853:5-hydroxydecanoic acid; C091375:9-phenanthrol; D007770:L-Lactate Dehydrogenase; D005947:Glucose