Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers -: Evidence for a dysfunctional nitric oxide synthase

Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 mu g/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.I. and 6.3 ng/100 mt tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) N-G-monomethyl-L-arginine (L-NMMA; 2, 4, and 8 mu mol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 mu g/100 mt tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant Vitamin C (6 and Is mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP, In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at, least in part to endothelial dysfunction in chronic smokers. The full text of this article is available at http://www.circresaha.org.