Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS). Oxidative stress oxidises BH4 to dihydrobioptein (BH2), resulting in the uncoupling of the two enzymatic domains of NOS and the production of superoxide rather than NO (NOS uncoupling). Oxidative stress is known to be increased in the early stage of chronic hypoxia. This study investigated the participation of NOS uncoupling in the early phase of hypoxia-induced pulmonary hypertension in rats. Rats were exposed to 10% O(2) for 4 days. We investigated the effect of BH4 in vitro on isolated rat lungs and isolated rat peripheral pulmonary blood vessels and in vivo on exhaled NO concentration in exhaled air. BH4 attenuated hypoxic pulmonary vasoconstriction in isolated lungs and its effect was reversed by l-NAME (NOS inhibitor). The main finding of the study is that the effect of BH4 was smaller in rats exposed to 4 days of hypoxia than in normoxic controls. The finding was similar in isolated pulmonary blood vessels. BH4 increased exhaled NO in both normoxic and hypoxic rats. This increase was blunted by l-NIL (specific iNOS inhibitor) and therefore attributable to iNOS. We conclude that BH4 increased NO production in both normoxic and hypoxic rats. The increase was, however, smaller in hypoxic lungs than in controls. We assume that the smaller increase in NO production in hypoxic lungs is due to the decreased BH4/BH2 ratio in chronic hypoxia and NOS uncoupling resulting from this condition.

Department of Physiology 2nd Medical School Charles University Prague Czech Republic

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