Nitric oxide (NO) is a short-lived vasodilator which serves a physiological role in the regulation of blood pressure and vascular tone. lmmunostimulants such as bacterial lipopolysaccharides (LPS), trigger overproduction of NO in the blood vessel, resulting in hypotension and often vascular collapse. lmmunostimulants also induce the synthesis of tetrahydrobiopterin (BH4) in various cell types; the function of induced BH4 and mechanisms for its induction have remained obscure Since BH4 is required for NO production, we hypothesize that the role of immunostimulant-induced BH4 is to support NO synthase. This view is strongly supported by preliminary studies. The overall goal of the proposed research is to understand the relationship between immunologically-evoked BH4 production and NO synthesis in vascular smooth muscle. Studies will elucidate: (1) the mechanistic basis for the BH4 requirement of NO synthase, (2) mechanism(s) for LPS-elicited BH4 synthesis, (3) the effect of BH4 and metabolites on the induction of NO synthase mRNA and protein by LPS, (4) the influence of NO on the induction of BH4 synthesis and metabolism by LPS, and, (5) the potential for therapeutic use of agents which interfere with BH4 synthesis for treatment of LPS-induced circulatory shock. The proposed studies will lead to an improved understanding of factors which regulate immunostimulant-induced NO production in the blood vessel wall. Moreover, we anticipate that our research will reveal novel pharmacotherapies, based on disruption of BH4 synthesis, which can be used to treat septic- and cytokine-induced shock.
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