Tetrahydrobiopterin in Pulmonary Hypertension Nitric Oxide in Pulmonary Hypertension

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All 3 NOS isoforms are expressed in the lung [62,66]. There is evidence that NO is involved in lung growth and development, in so far as eNOS knockout mice have defective lungs with a poorly developed air-blood barrier, which simulates the alveolar-capillary dysplasia [29]. Expression and activity of eNOS are developmentally regulated, with large increases in both in late gestation [62].

Loss of NO is implicated in pulmonary hypertension. Administration of NOS inhibitors, such as NG-nitro-L-arginine methyl ester (L-NAME), increases pulmonary vascular resistance and augments pulmonary vasoconstrictor responses to hypoxia [1]. Mice deficient in eNOS are more sensitive to hypoxia-induced pulmonary hypertension [19,73], whereas overexpression of eNOS in the lung is partially protective [63,13]. Patients with pulmonary hypertension have lower NO levels in their exhaled breath, a lower plasma L-citrulline/L-arginine ratio, lower urinary NO metabolites, and impaired endothelial-dependent vasorelaxation [42,50,56,26]. Furthermore, both inhaled NO and phosphodiesterase type 5 inhibitors, which act to increase NO-mediated cGMP signalling, have emerged as therapeutic options for pulmonary hypertension [23,38,89].

Reduced eNOS protein in lung tissues from patients with pulmonary hypertension has been described, which may again account for the low NO levels [24]. However, others have found normal or even increased levels of eNOS in their patients [54,91]. Indeed, mice with hypoxia-induced pulmonary hypertension have increased eNOS protein levels, without a concomitant increase in NO bioactivity [20,48]. These data suggest that eNOS may be dysfunctional rather than deficient.

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