Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers: Evidence for a Dysfunctional Nitric Oxide Synthase

• Published in: Circulation research 2000-02, Vol.86 (2), p.e36-e41
• Main Authors: Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Biopterins - analogs & derivatives; Biopterins - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Humans; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitroprusside - pharmacology; omega-N-Methylarginine - pharmacology; Regional Blood Flow - drug effects; Serotonin - pharmacology; Smoking - physiopathology; Vasodilation - drug effects
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.86.2.e36

ABSTRACTConditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability 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 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) N-monomethyl-L-arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL 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 18 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.