dimethylarginine and Hypertension--Pulmonary

We investigated whether infants with persistent pulmonary hypertension had elevated levels of asymmetric dimethyl arginine, an endogenous inhibitor of nitric oxide synthase, and symmetric dimethyl arginine, a regioisomer.. Prospective observational cohort study.. A 10-bed neonatal intensive care unit in a tertiary referral center.. Forty five infants >34 wks gestation and <2 wks old admitted to our intensive care unit.. Samples of urine on days 1, 3, and 5 were analyzed by high-performance liquid chromatography to determine asymmetric dimethyl arginine and symmetric dimethyl arginine levels. The clinical progression and treatment of the infants were noted.. Twenty-nine infants had a clinical diagnosis of persistent pulmonary hypertension confirmed on echocardiography, and there were 16 control infants. Median asymmetric dimethyl arginine levels on day 1 were significantly higher in the persistent pulmonary hypertension group (n = 29), 14.8 (10.3-21.7) mmol.mmol creatinine(-1).L(-1), compared with controls (n = 16), 3.6 (1.4-5.2) mmol.mmol creatinine(-1).L(-1) (p < .001). Asymmetric dimethyl arginine levels decreased to control levels by day 5 (p = .33). Symmetric dimethyl arginine levels were significantly higher than controls on day 1, 31.0 (21.7-65.9) vs. 14.7 (4.1-20.2) mmol.mmol creatinine(-1).L(-1) (p = .001) and day 3, 34.7(20.3-42.5) mmol.mmol creatinine(-1).L(-1) (p = .0001) and by day 5 had decreased significantly (p = .007) back to 16.7 (12.3-23.8) mmol.mmol creatinine(-1).L(-1), which was not significantly different than the control group values.. These results support the hypothesis that asymmetric dimethyl arginine and symmetric dimethyl arginine levels are elevated in patients with persistent pulmonary hypertension. Thus, endogenous inhibition of nitric oxide synthase by asymmetric dimethyl arginine may be responsible for the development of persistent pulmonary hypertension, suggesting novel therapeutic options in persistent pulmonary hypertension.

Topics: Arginine; Chromatography, High Pressure Liquid; Cohort Studies; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Intensive Care Units, Pediatric; Male; Nitric Oxide Synthase

This study was designed to investigate whether rosuvastatin could attenuate monocrotaline-induced pulmonary hypertension via regulation of Akt/eNOS signaling pathway and asymmetric dimethylarginine (ADMA) metabolism in rats. After a single-dose injection of monocrotaline (60 mg/kg), oral administration of rosuvastatin (5mg/kg) was started from day 1 to day 28 (preventive administration) or from day 15 to day 28 (therapeutic administration), or with vehicle as corresponding controls. 28 days after monocrotaline, significant pulmonary hypertension characterized by pulmonary arterial medial wall thickening, right ventricular hypertrophy and right heart failure was observed. Rosuvastatin (5mg/kg, for 14 days and 28 days) treatment significantly attenuated monocrotaline-induced pulmonary vascular remodeling, right ventricular hypertrophy and dysfunction, and normalized the down-regulated pulmonary Akt/p-Akt and eNOS/p-eNOS expressions, while increased DDAH2 expression accompanied by decreased serum level of ADMA. However expression of PRMT1 and GSK3β/p-GSK3β did not differ among all groups (all P>0.05). We concluded that rosuvastatin inhibits monocrotaline-induced pulmonary hypertension through normalization of Akt, eNOS and DDAH2 expressions, and decreasing the level of ADMA.

Topics: Amidohydrolases; Animals; Arginine; Biomarkers; Body Weight; Fluorobenzenes; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Nitric Oxide Synthase Type III; Organ Size; Protein-Arginine N-Methyltransferases; Proto-Oncogene Proteins c-akt; Pyrimidines; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium; Signal Transduction; Sulfonamides; Ventricular Dysfunction, Right

Local percutaneous tumor ablation with ethanol injection (PEI) under general anesthesia is an established therapy for patients with nonresectable hepatocellular carcinoma (HCC). There are reports of sudden hypotension immediately after PEI therapy, which was attributed to an acute increase in pulmonary vascular resistance. The aim of our study was to objectively confirm pulmonary hypertension by right heart catheterization and to evaluate biochemical markers with relevance to the pulmonary circulation.. Cross-sectional clinical study.. Interventional Gastroenterology in a tertiary care center.. We studied 40 patients with HCC who underwent percutaneous ethanol injection under general anesthesia for the treatment of nonresectable HCC.. In patients with HCC, PEI leads to a significant increase in pulmonary arterial pressure. Concomitantly, free hemoglobin and blood ethanol level significantly increased, whereas the l-arginine/asymmetric dimethylarginine ratio, a parameter of nitric oxide (NO) production capacity, and nitrite, a marker of NO synthesis, significantly decreased.. Procedure-related pulmonary hypertension in patients undergoing PEI is multifactorial. Plasma concentrations of the NO precursor l-arginine are reduced by arginase released from lysed erythrocytes, a condition further exacerbated by the increased concentrations of symmetric dimethylarginine, which may compete with the cellular uptake of l-arginine. The result would be reduced synthesis of NO, the concentration of which would be further decreased extracellularly through free hemoglobin. Predictably, the result would be severe endothelial dysfunction and pulmonary hypertension in patients undergoing PEI. These mechanisms might also be relevant in other states of (sudden) hemolysis.

Topics: Aged; Arginine; Carcinoma, Hepatocellular; Cross-Sectional Studies; Ethanol; Female; Hemolysis; Humans; Hypertension, Pulmonary; Injections; Liver Neoplasms; Male; Nitric Oxide

SSc is a CTD characterized by vascular involvement, with generalized disturbance of the microcirculation, which may lead to pulmonary artery hypertension (PAH). Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor. Increased concentrations of plasma ADMA may also contribute to endothelial dysfunction in patients with pulmonary vascular disease. The aim of our study was to elucidate the possible relationship between serum ADMA and PAH in patients with SSc. Moreover, we sought to investigate the effect of ADMA levels on the functional capacity of these patients.. Plasma ADMA levels were measured in 66 patients with SSc (63 females, mean age 57.8 +/- 12.8 yrs, median duration of disease 9.9 yrs, 47 with lcSSc and 19 with dcSSc disease) and 30 healthy controls (29 females, mean age 58.2 +/- 8.4 yrs). Systolic pulmonary artery pressure (sPAP) assessed by echocardiography, lung function tests, 6-min walk test (6MWT) and serum ADMA levels were recorded from patients.. In 24 patients, the diagnosis of PAH was established. Mean value of ADMA for SScPAH patients was 0.44 +/- 0.22 micromol/l compared with 0.26 +/- 0.18 micromol/l for patients without PAH and 0.25 +/- 0.20 micromol/l for controls (P = 0.001). ADMA levels were inversely correlated with the 6MWT (r = -0.55, P = 0.005).. In patients with SScPAH, increased ADMA serum levels and their negative association with exercise capacity suggests that the NO pathway is involved in the development of pulmonary vascular disease.

Topics: Aged; Analysis of Variance; Arginine; Case-Control Studies; Echocardiography; Echocardiography, Doppler; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Respiratory Function Tests; Scleroderma, Systemic

Nitric oxide (NO) has been suggested to play a key role in the pathogenesis of pulmonary hypertension (PH). To determine which mechanism exists to affect NO production, we examined the concentration of endogenous nitric oxide synthase (NOS) inhibitors and their catabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) activity and protein expression (DDAH1 and DDAH2) in pulmonary artery endothelial cells (PAECs) of rats given monocrotaline (MCT). We also measured NOS and arginase activities and NOS protein expression. Twenty-four days after MCT administration, PH and right ventricle (RV) hypertrophy were established. Endothelium-dependent, but not endothelium-independent, relaxation and cGMP production were significantly impaired in pulmonary artery specimens of MCT group. The constitutive NOS activity and protein expression in PAECs were significantly reduced in MCT group, whereas the arginase, which shares l-arginine as a common substrate with NOS, activity was significantly enhanced in PAECs of MCT group. The contents of monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA), were increased in PAECs of MCT group. The DDAH activity and DDAH1, but not DDAH2, protein expression were significantly reduced in PAECs of MCT group. These results suggest that the impairment of cGMP production as a marker of NO production is possibly due to the blunted endothelial NOS activity resulting from the downregulation of endothelial NOS protein, accumulation of endogenous NOS inhibitors, and accelerated arginase activity in PAECs of PH rats. The decreased overall DDAH activity accompanied by the downregulation of DDAH1 would bring about the accumulation of endogenous NOS inhibitors.

Topics: Amidohydrolases; Animals; Arginase; Arginine; Cyclic GMP; Endothelial Cells; Enzyme Activation; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Isometric Contraction; Lung; Male; Monocrotaline; Nitric Oxide; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasoconstriction

Topics: Arginine; Case-Control Studies; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Nitric Oxide Synthase