Decreased Whole Body Endogenous Nitric Oxide Production in Patients with Primary Pulmonary Hypertension

Abstract

Impaired pulmonary release of nitric oxide (NO) is one of the characteristic phenotypic changes of vascular cells in pulmonary hypertension. The aim of this study was to determine nitric oxide synthase (NOS)-dependent whole body NO production in patients with primary pulmonary hypertension. NOS-dependent whole body NO production was assessed by giving an intravenous infusion of L-[¹⁵N]₂-arginine (50 µmol/min for 30 min) and measuring isotopic urinary enrichment of ¹⁵N-nitrite and ¹⁵N-nitrate. Four female patients with no signs of infection were recruited and compared with 6 age-matched control subjects. Mean 12-hour excretion of ¹⁵N-nitrite and ¹⁵N-nitrate in the total urine over 36 h was smaller in patients than in control subjects (57.2 ± 27.6 vs. 229.1 ± 65.2 nmol/mmol creatinine, p< 0.01, Mann-Whitney U test, respectively). Neither mean 12-hour excretion of ¹⁴N-nitrite and ¹⁴N-nitrate (51.6 ± 10.0 vs. 72.4 ± 10.0 µmol/mmol creatinine, p = 0.3) nor glomerular filtration rates (84.5 ± 15.8 vs. 129.7 ± 16.0 ml/min, p = 0.1) were different between patients and control subjects. Our results suggest that either basal NOS-dependent whole body NO production is impaired or excess NO metabolism occurs in patients with primary pulmonary hypertension.

Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury

“…Although it is possible that this variable influenced the statistical analysis independent of NO, this is an unlikely scenario. First, the use of a ratio between a biomarker and urine Cr is a standard method to adjust for urinary dilution (28)(29)(30)(31). Second, in multivariate analyses that included estimated GFR, baseline urine NO/Cr remained highly predictive of better outcomes.…”

“…The Cr results obtained were also used to evaluate urine desmosine in these patients; those results have been reported elsewhere (27). The ratio of urine NO to urine Cr (NO/Cr) was used in the statistical analyses to control for urine dilution, a standard method when evaluating urine biomarkers (28)(29)(30)(31). Analyses using urine NO without Cr correction were performed for comparison.…”

Genistein, a Phytoestrogen, Attenuates Monocrotaline-Induced Pulmonary Hypertension

“…A recent study has shown a decrease in nitric oxide (NO) production after intravenous injection of L -arginine, a precursor for NO synthesis, in patients with primary PH, suggesting a possibility of impaired NO-mediated signaling [1]. Since impairment of NO-mediated signaling is considered as one of the causes of PH during the imbalance between endothelial mediators with opposing actions on pulmonary vasculature, inhaled NO has been used in the treatment of patients with PH.…”

Pulmonary Hypertension: Diagnosis and Management

“…These mechanisms are mediated by 1 or more molecular and cellular processes, including the following: reduced prostacyclin availability caused by diminished endothelial cell prostacyclin synthase activity 25 ; elevated endothelin levels resulting from enhanced production and reduced pulmonary clearance [26][27][28] ; decreased nitric oxide synthase expression 29,30 ; elevated plasma levels and low platelet 5-hydoxytryptamine levels 31 ; down-regulation of voltage-gated potassium (eg, Kv1.5) channels of pulmonary vascular smooth muscle cells 32,33 ; activity of autoantibodies and proinflammatory cytokines 34,35 ; and prothrombotic states arising from endothelial, coagulation, and fibrinolytic cascade and platelet dysfunction. [36][37][38][39] These abnormalities give rise to a predisposition to vasoconstriction over vasodilation of the pulmonary vascu-FIGURE 1.…”