Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers

Abstract

Abstract-Conditions 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 g/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 G -monomethyl-L-arginine (L-NMMA; 2, 4, and 8 mol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 g/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. (Circ Res. 2000;86:e36-e41.)

A weapon of endothelial cells for fighting vascular disease

“…Moreover, this supplementation effect has already been proven in smokers and patients with hypertension, hypercholesterolemia or chronic heart failure. [9][10][11] In this study, the authors examined the expression of GTPCH1, which is the rate-limiting enzyme in BH 4 synthesis, and the findings are consistent with those in previous reports. Recently, Higashi et al 12 also showed that the grade of oxidative stress correlates with BH 4 deficiency and that supplementation with BH 4 augmented endothelium-dependent vasodilation in the brachial arteries of elderly patients.…”

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

“…Various clinical studies have also demonstrated that administration of BH4 improves endothelial dysfunction in conditions characterized by reduced availability of NO and increased production of reactive oxygen species, such as hypercholesterolemia [38], coronary artery disease [24] and smoking [39]. BH4 is synthesized through 2 distinct pathways [16].…”

Redox Control of Renal Function and Hypertension

“…Nitrate tolerance and increased O 2 иϪ production was postulated to be due to eNOS uncoupling in long-term nitroglycerin treatment of rat aortic rings (226). Last, supplementation of BH 4 to insulin-resistant rats and chronic smokers improved their endothelium-dependent vasodilation, implicating eNOS uncoupling as the culprit mechanism (117,301). Oxidization of BH 4 by peroxynitrite (O 2 иϪ ϩ NO) and mutations in enzymes involved in BH 4 synthesis have been proposed as mechanisms active in vivo that can contribute to eNOS uncoupling (23).…”