Reduction of myocardial infarct size by tetrahydrobiopterin: possible involvement of mitochondrial KATP channels activation through nitric oxide production.
This study examined whether intravenous administration of tetrahydrobiopterin (BH4) reduces myocardial infarct size following ischemia/reperfusion (I/R) in rats, and the mechanisms of its protective effect were also investigated. Rats were subjected to 30 minutes of ischemia by ligation of the left coronary artery and 2 hours of reperfusion. The infarct size was determined as a percentage of the area at risk by triphenyltetrazolium staining. Intravenous administration of BH4 (0.01 mg/kg-1 mg/kg) significantly reduced the myocardial infarct size. Nitrite plus nitrate (NOx) and cGMP levels in the hearts were significantly increased by the treatment with BH4, and the infarct size-limiting effect of BH4 was abolished by the co-administration of NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, or 5-hydroxydecanoic acid, a specific inhibitor of mitochondrial ATP-sensitive potassium channel (mitoKATP channel). These findings suggest that BH4 has a cardioprotective effect against I/R in vivo, and its protective effect appeared to be involved in the opening of mitoKATP channels through increased nitric oxide production.
Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan.
Teruaki
T
Wajima
Shunichi
S
Shimizu
Toshihito
T
Hiroi
Masakazu
M
Ishii
Yuji
Y
Kiuchi
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000032:analysis; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000032:analysis; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D009566:Nitrates; D009573:Nitrites; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D001708:Biopterins; D009569:Nitric Oxide; D008315:Malondialdehyde; C052853:5-hydroxydecanoic acid; D001120:Arginine; C003402:sapropterin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester