Role of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts.
OBJECTIVE
It has recently been shown that nitric oxide synthase in the presence of suboptimal levels of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide synthase, may favor increased production of oxygen free radicals. This study was designed to define the role of BH(4) in myocardial ischemia-reperfusion injury.


METHODS
Isolated perfused rat hearts were subjected to 37 degrees C ischemia and reperfusion. Hearts were received with BH(4) or vehicle for 5 min just before ischemia and during the first 5 min of the reperfusion period. The effects of BH(4) on left ventricular function, myocardial contents of lipid peroxidation and high energy phosphates, and levels of lactate dehydrogenase and nitrite plus nitrate in perfusate before ischemia and after reperfusion were estimated. Moreover, the effect of BH(4) given with 2,4-diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of BH(4) production, intraperitoneally 24 h before the experiments were estimated.


RESULTS
BH(4) improved contractile and metabolic abnormalities in reperfused hearts. Furthermore, BH(4) significantly alleviated ischemic contracture during ischemia, and restored diminished perfusate levels of nitrite plus nitrate after reperfusion. On the other hand, DAHP-treatment aggravated ischemia-reperfusion induced functional and metabolic abnormalities. Administration of BH(4) improved DAHP-induced functional and metabolic abnormalities.


CONCLUSIONS
Results demonstrated that BH(4) lessens ischemia-reperfusion injury in isolated perfused rat hearts. Conversely, deficiency of BH(4) seems to accelerate endothelial dysfunction and myocardial ischemia-reperfusion injury. Present data may be compatible with the hypothesis that nitric oxide synthase in the presence of insufficiency of BH(4) serve as the cause of oxidative injury.
Yamashiro
S
S
2ndDepartment of Surgery, School of Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Noguchi
K
K
Kuniyoshi
Y
Y
Koja
K
K
Sakanashi
M
M
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D007042:Hypoxanthines / Q000494:pharmacology; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D007042:Hypoxanthines; D001708:Biopterins; D009569:Nitric Oxide; C017202:2,4-diaminohypoxanthine; C003402:sapropterin