Handbook of Vitamin C Research

Protective Effect of Vitamin C 335Figure 2.various antioxidants enzymes would probably result in impaired antioxidant defences by cellsand render more vulnerable to oxidative attacks.The main receptor of nitric oxide is soluble guanylate cyclase which after nitrite oxidebinding generates cyclic GMP (cGMP). cGMP acts as second messenger to stimulate thenitric oxide dependent vasorelaxation. Khalil-Manesh et al. demonstrated an induced plasmaand urinary concentration of cGMP in rats with-lead induced hypertension [44]. Marques etal. showed that, despite upregulation of endothelial nitric oxide synthase (eNOS), thevasorelaxation response to acetylcholine was reduced in isolated aortic from lead-exposedrats. It was accompanied by an impaired vasodilatory response to exogenous nitric oxide inlead-exposed rats. It was also associated with reduction in the vascular expression of both 1and 1 soluble guanylate cyclase subunits in the vascular wall of lead-exposed rats [45].These findings further confirmed in in vitro lead-exposed vascular smooth muscle cells whichshowed downregulation of the soluble guanylate cyclase after lead exposure. In lead-induceddownregulation may be also involved the release of endothelin from the endothelium. In thisregard, Molero et al. found that incubation with an endothelin type A receptor antagonistpartially reversed lead-induced downregulation of soluble guanylate cyclase and cGMPproduction [46] (Figure 2).COX-2Free radicalsNOcAMPcGMPFigure 2. Proposed mechanism by which lead induced downregulation of soluble guanylate cyclaseexpression in the vascular well. In brief, free radicals stimulated cycloxygenase-2 expression whichincreased cyclic AMP production. Cyclic AMP downregulates soluble guanylate cyclase expression.3. Vitamin C and Cardiovascular Protectionagainst Mercury and LeadReactive oxygen species (e.g., superoxide, hydrogen peroxide and hydroxyl radical) areintermediary metabolites that are normally produced in the course of oxygen metabolism. Anexcess in the production of oxygen species and/or impaired antioxidant defence capacityleads to oxidative stress. Hypertension is one of the main risk cardiovascular factors. There is