TETRAHYDROBIOPTERIN, NITRIC-OXIDE AND REGULATION OF CEREBRAL ARTERIALTONE

Tetrahydrobiopterin is an essential cofactor required for activity of nitric oxide synthases. Existing evidence suggests that, during activa tion of constitutive and inducible isoforms of nitric oxide synthase, tetrahydrobiopterin is needed for allosteric and redox activation of e nzymatic activity. However, precise mechanisms underlying the role of tetrahydrobiopterin in regulation of nitric oxide formation is not ful ly understood. In cerebral and peripheral arteries, increased availabi lity of tetrahydrobiopterin can augment production of nitric oxide. In contrast, in arteries depleted of tetrahydrobiopterin, production of nitric oxide is impaired. Proinflammatory cytokines enhance mRNA expre ssion of the rate-limiting enzyme of tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I and stimulate production of tetrahydrobiopterin. The ability of vascular tissues to synthesize tetrahydrobiopterin pla ys an important role in regulation of nitric oxide synthase under phys iological conditions as well as during inflammation and sepsis. More r ecent studies concerning expression and function of recombinant nitric oxide synthases suggest that availability of tetrahydrobiopterin is i mportant for production of nitric oxide in genetically engineered bloo d vessels. In this review, mechanisms regulating availability of intra cellular tetrahydrobiopterin and its role in control of vascular tone under physiological and pathological conditions will be discussed. (C) 1997 Elsevier Science Ltd. All rights reserved.