Background-Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor L-arginine is related to decreased endothelial function. Methods and Results-Radiotracer kinetics ([3 H]L-arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (nϭ12) and in 2 groups of healthy volunteers with (nϭ15) and without (nϭ15) a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of L-arginine. In vivo and in vitro measures of L-arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group; however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of L-arginine and N G ,N GЈ -dimethylarginine (ADMA) did not differ between groups. L-Arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. Conclusions-Similar

Abstract-Endothelial dysfunction is a hallmark of cardiovascular disease, and the L-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with L-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (Pϭ0.01) than nonsmokers, whereas citrulline (17%; PϽ0.05) and N-hydroxy-L-arginine (34%; PϽ0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-L-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial L-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease. Key Words: smoking Ⅲ endothelium Ⅲ metabolism A therosclerotic coronary and cerebrovascular disease are leading causes of death and disability in the Western world, and cigarette smoking has been clearly identified as a risk factor for coronary artery disease (reviewed by Ambrose and Barua 1 ). In this context, measures of endothelial function have been associated with cardiovascular outcome, 2 and smoking has been widely associated with reduced endothelial function. 3 The endothelium plays a central role in the modulation of vascular tone, the inhibition of platelet aggregation and vascular smooth muscle proliferation, and a key participation in angiogenesis under appropriate conditions. NO is well recognized as playing a pivotal part in these endothelial properties, being produced by the endothelial isoform of NO from its preferred substrate L-arginine. In this context, provision of sufficient L-arginine is critical for the sustained production of NO supply, 4 mediated in endothelial cells (ECs) principally by the type 1 cationic amino acid transporter (CAT1). Previous studies indicate that deleterious actions of cigarette smoke on endothelial function could be mitigated by supplemental L-arginine; 5 however, to date, the precise basis for this interaction remains unclear. One explanation is that cigarette smoke exerts an inhibitory effect on components of the L-arginine:NO pathway to influence NO production. In addition, potential effects of cigar...

No abstract

Hyperuricemia is a risk factor for gout. It has been well observed that a large proportion of individuals with hyperuricemia have never had a gout flare(s), while some patients with gout can have a normuricemia. This raises a puzzle of the real role of serum uric acid (SUA) in the occurrence of gout flares. As the molecule of uric acid has its dual effects in vivo with antioxidant properties as well as being an inflammatory promoter, it has been placed in a delicate position in balancing metabolisms. Gout seems to be a multifactorial metabolic disease and its pathogenesis should not rely solely on hyperuricemia or monosodium urate (MSU) crystals. This critical review aims to unfold the mechanisms of the SUA role participating in gout development. It also discusses some key elements which are prerequisites for the formation of gout in association with the current therapeutic regime. The compilation should be helpful in precisely fighting for a cure of gout clinically and pharmaceutically.