Effects of cytokines on nitric oxide pathways in human vasculature

Proinflammatory cytokines exert a number of important effects on vascular r eactivity. At one end of the spectrum, certain cytokines may induce vascula r paresis leading to profound vasodilatation and hyporesponsiveness to cons trictor stimuli. This may be relevant to the pathogenesis of septic shock a nd other types of inflammatory vasodilatation. At the other end of the spec trum, inflammatory cytokines can impair endothelium-dependent dilatation an d the endothelium may lose its ability to respond to circulating hormones o r autacoids. This effect may case a predisposition to vessel spasm, thrombo sis or atherogenesis. Studies in human vessels suggest that interleukin-l i s particularly important as a mediator of inflammatory dilatation; the unde rlying mechanisms include induction of the inducible isoform of nitric oxid e synthase in vascular smooth muscle, or over-production of nitric oxide fr om the endothelial isoform of nitric oxide synthase. Induction of the enzym e GTP cyclohydrolase 1 and consequent production of tetrahydrobiopterin con tributes to the increase in the activity of endothelial nitric oxide syntha se. In contrast, tumour necrosis factor-a considerably impairs endothelium- dependent relaxation. The mechanisms of these effects are not yet fully und erstood, but tumour necrosis factor can induce endothelial dysfunction in h uman endothelial cells in culture, and human blood vessels in vitro and in vivo. The implications of these observations for cardiovascular disease are discussed. Curr Opin Nephrol Hypertens 8:89-98. (C) 1999 Lippincott Willia ms & Wilkins.