The effect of insufficiency of tetrahydrobiopterin on endothelial function and vasoactivity

Objective: It has recently been defined that levels of tetrahydrobiopterin, a cofactor of nitric oxide synthase, decreases under some disease conditions including atherosclerosis, hypercholesterolemia, diabetes, and ischemia-reperfusion. The present study was designed to investigate whether or not a deficiency in tetrahydrobiopterin affected vasoactivation in vivo and in vitro.Subjects and Methods: Male Sprague-Dawley rats were divided into two groups, and given either 2, 4-diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of tetrahydrobiopterin production, or a vehicle (10% polyethylene glycol 400 in 5% glucose, 20 ml/kg), intraperitoneally at 24 hr prior to examination. Responses to several vasodilating agents were examined in both pretreatment groups in vivo and in vitro. Furthermore, the isolated heart was perfused with a 37°C Krebs-Henseleit solution for 30 min. The effects of insufficient tetrahydrobiopterin on the left ventricular function were examined. Moreover, nitrite plus nitrate (NOx) in the coronary effluent was examined in both groups.Results: Depressor and vasodilatation responses to an endothelium-dependent vasodilator were significantly attenuated in the DAHP Group in comparison with those in the vehicle Control Group, while the endothelium-independent vasodilator caused equivalent depressor and vasodilatation responses between the two groups. The NOx levels in the coronary effluent were lower in the DAHP Group than in the Control Group (p<0.05). The cardiovascular parameters were also lower in the DAHP Group than in the Control Group. Conclusions: We concluded from these findings that a deficiency in tetrahydrobiopterin aggravated endothelial dysfunction and the left ventricular dysfunction. These findings were consistent with the hypothesis that decreased levels of tetrahydrobiopterin may cause cardiac and vascular dysfunction.