[Effect of hypoxia on distribution and activity of nitric oxide synthase in rat lung]

Nitric oxide is an important cellular messenger molecule that has been implicated in a wide range of physiological and pathophysiological actions in cardiovascular, immune, and nervous systems. Nitric oxide synthase (NOS) is the sole and key enzyme responsible for the generation of nitric oxide. The effect of hypoxia-induced pulmonary hypertension on NOS in the lung is controversial. To clarify the effect of hypoxia on distribution and activity of NOS in rat lung, localization of NOS in the lungs of hypoxic and normoxic rats were studied using NADPH-diaphorase histochemical staining techniques, NOS enzyme activity in the lung homogenates was assessed by [3H] arginine to [3H] citrulline conversion. In the normoxic rat, NADPH-d was distributed in the endothelial cells of large pulmonary vessels (ID > 150 microns) and medium-sized (50 microns < ID < 150 microns) vessels but was not detected in the endothelium of small vessels (ID < 50 microns), and there was an absence of NADPH-d staining in the smooth muscle cells of small, medium, and large pulmonary vessels. However, after hypoxic exposure for two weeks, NADPH-d staining increased dramatically in the endothelial cells of large and medium-sized pulmonary vessels, and NADPH-d became markedly positive in the endothelial cells of small vessels. Hypoxia was also found to induce de novo NOS expression in the smooth muscle cells of small, medium-sized, and large pulmonary vessels. The enzyme activity of constitutive NOS(cNOS) was decreased obviously in the hypoxic rat lungs, but that of inducible NOS(iNOS) was increased significantly in the hypoxic rat lungs. These results suggested that the inhibited endothelium-derived relaxing factor (EDRF)/NO-dependent vasodilation after hypoxic exposure might be induced by decreased activity of cNOS in the endothelium of pulmonary vessels, and hypoxia-induced upregulation of iNOS expression and activity in the rat lung might play an important role in the adaptation of pulmonary circulation to hypoxia.