Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction

Abstract

Tetrahydrobiopterin (BH(4)) is an essential cofactor for nitric oxide synthases (NOS). This study investigated the effect of increasing BH(4) levels on hypoxia-induced pulmonary vasoconstriction (HPV). Sprague Dawley rats and hph-1 (BH(4) deficient) mice were given BH(4) before and during HPV in an isolated perfused lung preparation. BH(4) inhibited HPV in a concentration-dependent manner and increased NO metabolites in the perfusate. Bradykinin-induced reductions in HPV were blunted in hph-1 mice and pre-administration of BH(4) restored the response. The effect of BH(4) was attenuated by l-NAME (NOS inhibitor), PTIO (NO scavenger), and catalase (H(2)O(2) catalyser) administered prior to HPV but enhanced by MnTMPyP (superoxide dismutase mimetic). The effect of BH(4) on HPV was partially recapitulated by NH(4), a stereoisomer that shares antioxidant properties with BH(4) but is not a NOS cofactor. The bioavailability of BH(4) is an important determinant of the pulmonary vascular response to hypoxia. Its effects are mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. Pharmacological administration of BH(4) may have therapeutic potential in pulmonary hypertension.