Regulation of alveolar gas conductance by NO in man, as based on studies with NO donors and inhibitors of NO production

Aim: Nitric oxide (NO) is a mediator of the pulmonary vessel tone and permeability. We hypothesized that it may also regulate the alveolar-capillary membrane gas conductance and lung diffusion capacity. Methods: In 20 healthy subjects (age = 23 ± 3 years) we measured lung diffusion capacity for carbon monoxide (DLco), its determinants (membrane conductance, D_m, and pulmonary capillary blood volume, V_c), systolic pulmonary artery pressure (PAPs) and pulmonary vascular resistance (PVR). Measurements were performed before and after administration of N^g-monomethyl-l-arginine (l-NMMA, 0.5 mg kg^-1 min^-1), as a NO production inhibitor, and l-arginine (l-Arg, 0.5 mg kg^-1 min¹) as a NO pathway activator. The effects of l-NMMA were also tested in combination with active l-Arg and inactive stereoisomer d-Arg vehicled by 150 mL of 5%d-glucose solution. For l-Arg and l-NMMA, saline (150 mL) was also tested as a vehicle. Results: l-NMMA reduced D_m (-41%P <0.01), DLco (-20%, P <0.01) and cardiac output (CO), and increased PAPs and PVR. In 10 additional subjects, a dose of l-NMMA of 0.03 mg kg^-1 min¹ infused in the main stem of the pulmonary artery was able to lower D_m (-32%, P <0.01) despite no effect on PVR and CO. D_m depression was significantly greater when l-NMMA was vehicled by saline than by glucose. l-Arg but not d-Arg abolished the effects of l-NMMA. l-Arg alone increased D _m (+14%, P <0.01). Conclusion: The findings indicate that NO mediates the respiratory effects of l-NMMA and l-Arg, and is involved in the physiology of the alveolar-capillary membrane gas conductance in humans. NO deficiency may cause an excessive endothelial sodium exchange/water conduction and fluid leakage in alveolar interstitial space, lengthening the air-blood path and depressing diffusion capacity.