Disruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchyma

作者：Sopi Ramadan B; Haxhiu Musa A; Martin Richard J; Dreshaj Ismail A; Kamath Suneel; Zaidi Syed I A^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2007, 293(4): L1029-L1036.

DOI：10.1152/ajplung.00182.2007

• arginase
• L-arginine
• N-omega-nitro-L-arginine methyl ester
• lung strips
• nitric oxide synthase

Exposure of immature lungs to hyperoxia for prolonged periods contributes to neonatal lung injury and airway hyperreactivity. We studied the role of disrupted nitric oxide- guanosine 3', 5'-cyclic monophosphate ( NO-cGMP) signaling in impairing the relaxant responses of lung tissue from hyperoxia-exposed rat pups. Pups were exposed to >= 95% O-2 or room air for 7 days starting from days 1, 5, or 14. The animals were killed, lungs were removed, and 1-mm-thick lung parenchymal strips were prepared. Lung parenchymal strips of room air or hyperoxic pups were preconstricted using bethanechol and then graded electrical field stimulation ( EFS) was applied to induce relaxation. EFS-induced relaxation of lung parenchymal strips was greater at 7 and 12 days than at 21 days in room air-exposed rat pups. Hyperoxic exposure significantly reduced relaxation at 7 and 12 days but not 21 days compared with room air exposure. NO synthase blockade with N(omega)nitro-L-arginine methyl ester diminished relaxant responses in room air but not in hyperoxic pups at 12 days. After incubation with supplemental L-arginine, the relaxation response of hyperoxic strips was restored. cGMP, a key mediator of the NO signaling pathway, also decreased in strips from hyperoxic vs. room air pups and cGMP levels were restored after incubation with supplemental L-arginine. In addition, arginase activity was significantly increased in hyperoxic lung parenchymal strips compared with room air lung parenchymal strips. These data demonstrate disruption of NO-cGMP signaling in neonatal rat pups exposed to hyperoxia and show that bioavailability of the substrate L-arginine is implicated in the predisposition of this model to airway hyperreactivity.

• 出版日期2007-10