Transpulmonary vascular gradients of nitric oxide pathway metabolites and asymmetrical dimethyl-L-arginine in the flow – or pressure-overloaded pulmonary vasculature

Objectives

Alterations in pulmonary vascular nitric oxide (NO) production have been implicated in the regulation of pulmonary vascular tone and the development of pulmonary hypertension (PH). Asymmetrical dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO synthesis, has been suggested to counteract endothelial NO production.

Methods

Transpulmonary gradients of nitrite (NO₂), nitrate (NO₃) and ADMA were determined in patients with increased pulmonary flow (Qp) before (1) and after (2) interventional closure of atrial septal defect (ASD), and in patients with increased pulmonary vascular resistance (Rp) (3). Twenty patients with ASD: median age 6.1 years (range 3.5–17.1 years), median Qp/Qs 2.1, Rp/Rs < 0.12. Twenty patients with PH: median age 8.1 years (range 1.2–13.5 years), median Rp/Rs 1.1 (range 0.36–1.79). NO₂, NO₃ (chromatography mass spectrometry) and ADMA (high-performance liquid chromatography) were measured in plasma samples from the main pulmonary artery (PA) and femoral artery (SA).

Results

(1) In ASD patients, NO₂ showed a significant gradient with a median SA : PA ratio of 1.34 (P < 0.01), but this was not so for ADMA (1.05) or NO₃ (1.01). (2) After closure, SA : PA ratio of NO₂ decreased to 0.89 (P < 0.05), indicating a switch from NO₂ production to NO₂ consumption, whereas ADMA (1.00) and NO₃ (0.99) remained unchanged. (3) In PH, significant transpulmonary gradients were observed for ADMA (1.11; P < 0.05) and NO₃ (1.03), but not for NO₂ (0.84). Median levels of ADMA in SA (4.08 μmol/l) were higher than those in ASD before (3.67 μmol/l) and after (3.55 μmol/l) closure (P < 0.05).

Conclusions

Analysis of transpulmonary metabolite gradients may provide significant insights into the vascular NO pathway in the overloaded pulmonary circulation. Reversible augmentation of intra-pulmonary vascular NO synthesis in ASD patients contrasts with the inappropriate NO synthesis in patients with increased Rp, to which intrapulmonary ADMA formation may significantly contribute.