scholarly journals Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Shiro Mizuno ◽  
Takeshi Ishizaki ◽  
Hirohisa Toga ◽  
Akio Sakai ◽  
Jainagul Isakova ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Vascular Tone ◽  
Asymmetric Dimethylarginine ◽  
Adverse Outcomes ◽  
Enos Expression ◽  
Mountain Areas ◽  
Plasma Adma ◽  
Pulmonary Arterial ◽  
Adma Concentration

Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

scholarly journals Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude

2000 ◽  
Vol 279 (4) ◽  
pp. H2013-H2016 ◽  
Author(s):  
Yves Allemann ◽  
Claudio Sartori ◽  
Mattia Lepori ◽  
Sébastien Pierre ◽  
Christian Mélot ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Doppler Echocardiography ◽  
Systolic Pulmonary Arterial Pressure ◽  
Wide Range ◽  
High Altitude Pulmonary Edema ◽  
Reproducible Method ◽  
Pulmonary Arterial ◽  
Spearman Test ◽  
Invasive Measurement

Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 ± 12 and 58 ± 10 mmHg for noninvasive and invasive determination, respectively; means ± SD) than subjects resistant to HAPE (37 ± 8 and 37 ± 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30–83 mmHg). Spearman test showed a highly significant correlation ( r = 0.89, P < 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 ± 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement.

scholarly journals Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery

2012 ◽  
Vol 49 (6) ◽  
pp. 589-594 ◽  
Author(s):  
R Patle ◽  
S Dubb ◽  
J Alaghband-Zadeh ◽  
R A Sherwood ◽  
F Tam ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Bariatric Surgery ◽  
Weight Loss ◽  
Asymmetric Dimethylarginine ◽  
Obese Patients ◽  
Endogenous Inhibitor ◽  
Nitrite Concentration ◽  
Plasma Adma ◽  
Adma Concentration

Background Obesity is associated with hypertension, but the exact mechanism is not fully understood. Bariatric surgery significantly decreases weight and blood pressure (BP). Low plasma nitric oxide (NO) and raised asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO, concentrations are associated with both obesity and hypertension. Correlations between the changes in these parameters were studied after bariatric surgery. Methods Weight, BP, plasma ADMA and NO were measured in 29 obese patients (24 female, 5 male) before and six weeks after bariatric surgery. Results Patients were 39.2 ± 1.2 (mean ± SEM) years old and weighed 126 ± 3 kg. Six weeks after the surgery, patients had lost 10 ± 0.7 kg ( P < 0.0001) and mean arterial pressure (MAP) decreased by 11 ± 1.0 mmHg ( P < 0.0001). The plasma ADMA concentration decreased by 24 ± 2% from 5 ± 0.4 to 4.0 ± 0.3 μmol/L ( P < 0.0001). The plasma total nitrite concentration increased by 15 ± 1% from 51.4 ± 2.6 to 60 ± 3 μmol/L ( P < 0.0001). The correlation between the decrease of ADMA and increase of NO subsequent to weight loss was significant ( P < 0.0001). However, MAP was not correlated to the changes in ADMA or NO. Conclusions After bariatric surgery, beneficial changes in BP, NO and ADMA occur, but our findings suggest that these BP changes are independent of changes in the NO–ADMA axis. Other causes for the changes in BP should therefore be considered.

Contribution of peptidyl prolyl isomerase (Pin1) to development of pulmonary hypertension via pulmonary vascular endothelial cell dysfunction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Sakai ◽  
H Maruyama ◽  
M Ieda
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Western Blot ◽  
Caspase 3 ◽  
Pulmonary Arterial Pressure ◽  
Funding Source ◽  
Enos Expression ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is thought to be a major contributor to overall pathogenesis of vasculopathy seen in pulmonary hypertension (PH), which is manifested by the impaired release of nitric oxide (NO) generated through endothelial nitric oxide synthase (eNOS) in endothelial cells. Activation of human eNOS is regulated by phosphorylation at multiple sites including Thr33 and Ser114, which residues are followed by Pro. The peptidyl isomerase Pin1 specifically isomerizes the phospho-protein having Ser/Thr-Pro bond and regulates their activity. Pin1 is involved in proliferation, cell cycle, and apoptosis in cancer, by isomerizing some functional molecules such as JNK, JUN, cyclin D, BAX, etc. However, it is controversial whether direct interaction of Pin1 with eNOS and how eNOS activity is altered by Pin1, especially in PH. Purpose We aimed to clarify whether Pin1 contributes to the PH development using Pin1 knockout mice and Pin1 affects the expression of phosphorylated eNOS (p-eNOS) molecule and pulmonary arterial endothelial cell (PAEC) apoptosis. Methods and results Wild (WT) and Pin1-deficient mice (KO) were exposed to hypoxia (10% O2) or normoxia for 3 weeks to generate hypoxia-induced PH. Hypoxia-inducible factor (HIF1α) expression in lungs was significantly enhanced in WT-hypoxia (WH, n=6) and KO-hypoxia (KH, n=6), suggesting that hypoxic response was certainly occurred in these mice. Pulmonary arterial pressure did not elevate in KH compared with KO-normoxia (KN, n=6) and WT-normoxia (WN, n=6), it was significantly increased only in WH (P&lt;0.01), indicating that KO did not develop PH by hypoxia. The gain of RV weight was parallel to the increase of pulmonary arterial pressure. Western blot showed that p-eNOS expression in lungs was significantly decreased in WH compared to WN, however, the expression was not different between KH and KN. It suggests that Pin1 plays a regulatory role in p-eNOS expression in hypoxic response. In cultured PAECs, the expression of p-eNOS and eNOS was markedly increased by siRNA-mediated Pin1 knockdown. Immunoprecipitation study showed the possibility of Pin1 binding to p-eNOS molecule. Apoptosis evaluated by caspase-3/7 activity by fluorescent assay and cleaved caspase-3 expression by Western blot was significantly increased by Pin1 overexpression in PAECs; however, it was significantly decreased by Pin1 knockdown. Moreover, the exaggeration of apoptosis induced by doxorubicin was markedly increased by Pin1 overexpression compared with control in PAECs; however, it was clearly suppressed by Pin1 knockdown. Conclusion This study suggests that endogenous Pin1 contributes to the development of PH partly via the dysfunction of PAECs, that is, by the interference with p-eNOS expression and by the increase of apoptosis inducibility to external stimuli. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

P6480Asymmetric dimethylarginine (ADMA) predicts altitude-associated hypoxic pulmonary arterial hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R H Boeger ◽  
P Siques ◽  
J Brito ◽  
E Schwedhelm ◽  
E Pena ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Logistic Regression ◽  
Oxygen Saturation ◽  
High Altitude ◽  
Sea Level ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Arterial Blood ◽  
Pulmonary Arterial

Abstract Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) is an important regulator of systemic and pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis that increases in hypoxia, we aimed to investigate whether ADMA predicts the incidence of HAPH among Chilean frontiers personnel exposed to six months of CIH. We performed a prospective study of 123 healthy male subjects who were subjected to CIH (5 days at appr. 3,550 m, followed by 2 days at sea level) for six months. ADMA, SDMA, L-arginine, arterial oxygen saturation, systemic arterial blood pressure, and haematocrit were measured at baseline and at months 1, 4, and 6 at high altitude. Acclimatization to high altitude was determined using the Lake Louise Score and the presence of acute mountain sickness (AMS). Echocardiography was performed after six months of CIH in a subgroup of 43 individuals with either good (n=23) or poor (n=20) aclimatization to altitude, respectively. Logistic regression was used to assess the association of biomarkers with HAPH. 100 study participants aged 18.3±1.3 years with complete data sets were included in the final analysis. Arterial oxygen saturation decreased upon the first ascent to altitude and plateaued at about 90% during the further course of the study. Haematocrit increased to about 47% after one month and remained stable thereafter. ADMA continuously increased and SDMA decreased during the study course, whilst L-arginine levels showed no distinct pattern. The incidence of AMS and the Lake Louise Score were high after the first ascent (53 and 3.1±2.4, respectively) and at one month of CIH (47 and 3.0±2.6, respectively), but decreased to 20 and 1.4±2.0 at month 6, respectively (both p<0.001 for trend). In echocardiography, 18 participants (42%) showed a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg (mean ± SD, 30.4±3.9 mm Hg), out of which 9 (21%) were classified as HAPH (mPAP ≥30 mm Hg; mean ± SD, 33.9±2.2 mm Hg). Baseline ADMA, but not SDMA, was significantly associated with mPAP at month 6 in univariate logistic regression analysis (R = 0.413; p=0.007). In ROC analysis, a cut-off for baseline ADMA of 0.665 μmol/l was determined as the optimal cut-off level to predict HAPH (mPAP >30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. ADMA concentration increases during long-term CIH. It is an independent predictive biomarker for the incidence of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of high altitude pulmonary hypertension. Acknowledgement/Funding CONICYT/FONDEF/FONIS Sa 09I20007; FIC Tarapaca BIP 30477541-0; BMBF grant 01DN17046 (DECIPHER); Georg & Jürgen Rickertsen Foundation, Hamburg

Alteration of the pulsatile load in the high-altitude calf model of pulmonary hypertension

1991 ◽  
Vol 70 (2) ◽  
pp. 859-868 ◽  
Author(s):  
B. D. Zuckerman ◽  
E. C. Orton ◽  
K. R. Stenmark ◽  
J. A. Trapp ◽  
J. R. Murphy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
High Altitude ◽  
Arterial Wall ◽  
Arterial Compliance ◽  
Arterial Elasticity ◽  
Arterial Distensibility ◽  
Pulmonary Arterial ◽  
Pulsatile Load ◽  
The Right

We compared main pulmonary arterial elasticity and global pulmonary arterial compliance in control and high-altitude (HA) calves to determine whether 1) changes in pulmonary arterial elasticity are contributing to an increase in the oscillatory load of the right ventricle in this model of pulmonary hypertension and 2) measured changes in stiffness of the HA calves' arterial wall are the result of both an increase in pressure and an alteration of the material properties of the HA calves' arterial wall. Newborn calves were placed at 4,300 m simulated altitude for 14 days, and control calves were kept at 1,500 m. The HA calves were then reacclimatized to 1,500 m for 24 h so that baseline pressures of the two groups were similar. Open-chest main pulmonary arterial and right ventricular micromanometric pressures, ultrasonic main pulmonary arterial diameter, and green dye flow were measured under baseline conditions and then under moderate and severely hypoxic conditions to make measurements at both baseline and increased pulmonary pressures. At elevated pressures, the pressure-diameter relationship was noted to be nonlinear, and a characteristic late systolic peaking of the right ventricular pressure waveform was seen. The Peterson pressure-strain modulus, pulse wave velocity, characteristic impedance, and global compliance (3 element windkessel) were calculated. The calculated variables were all shown to be pressure dependent, and no intrinsic differences in stiffness were seen between the control and HA animals when mean pressure was taken into account. Pulmonary arterial histology demonstrated, however, a characteristic increase in wall thickness in the HA animals. Thus, in this model of pulmonary hypertension, major changes in elasticity and pulsatile load are primarily due to an increase in pulmonary pressure. The structural changes present in the HA calves' arterial wall did not separately produce any measurable changes in arterial distensibility or the oscillatory load.

Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude

1988 ◽  
Vol 65 (6) ◽  
pp. 2632-2640 ◽  
Author(s):  
R. F. Grover ◽  
R. L. Johnson ◽  
R. G. McCullough ◽  
R. E. McCullough ◽  
S. E. Hofmeister ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Sea Level ◽  
Vascular Reactivity ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Prostaglandin Synthesis ◽  
Inhibition Of Prostaglandin Synthesis ◽  
Pulmonary Arterial ◽  
Low Altitude

It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.

Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure

2002 ◽  
Vol 103 (s2002) ◽  
pp. 241S-244S ◽  
Author(s):  
Masato OHNISHI ◽  
Atsuyuki WADA ◽  
Takayoshi TSUTAMOTO ◽  
Masanori FUJII ◽  
Takehiro MATSUMOTO ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Asymmetric Dimethylarginine ◽  
No Production ◽  
Plasma Adma ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Synthase Inhibitor ◽  
Regulation Of Vascular Tone

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n = 5; 270beats/min) compared with normal dogs (n = 5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56±0.16 compared with 2.93±0.25litres/min; P<0.01) and systemic vascular resistance had increased (4653±374 compared with 3227±396dyn·s·cm-5; P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95±0.83 compared with 2.12±0.39pg/ml; P<0.05) and ADMA (3.27±0.49 compared with 1.91±0.25nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r = 0.72, P<0.05). Secondly, we chronically administered an ETA receptor antagonist, TA-0201 (0.3mg/kg; n = 5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58±0.24litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36±0.30nmol/ml and 2423±188dyn·s·cm-5 respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ETA receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.

scholarly journals From the Andes to the Rocky Mountains: A Historical View of High-Altitude Pulmonary Hypertension

2020 ◽  
Vol 19 (3) ◽  
pp. 72-76
Author(s):  
Christopher H. Chang ◽  
Jeffrey C. Robinson
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Rocky Mountains ◽  
Pulmonary Vascular Disease ◽  
Distinct Entity ◽  
Historical View ◽  
The Andes ◽  
Clinical Models ◽  
Pulmonary Arterial ◽  
Models Of Disease

The current understanding of high-altitude pulmonary hypertension (HAPH) is largely attributable to the work of a small cadre of international scientists. The present article discusses the discovery and early investigations into HAPH that now serve as the foundation of our modern understanding of the disease. Further, though HAPH is clearly a distinct entity, we highlight how this early work led to a broader understanding of pulmonary vascular disease—including pulmonary arterial hypertension (PAH)—through the development of translational clinical models of disease, elucidation of hypoxic signaling, and therapeutics applicable to PAH.

ASYMMETRIC DIMETHYLARGININE PLASMA IN END STAGE CHRONIC KIDNEY DISEASE

2016 ◽  
pp. 72-77
Author(s):  
Trong Ai Quoc Hoang ◽  
Tam Vo ◽  
Viet Thang Hoang
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Serum Creatinine ◽  
Asymmetric Dimethylarginine ◽  
Healthy People ◽  
Serum Creatinine Concentration ◽  
Creatinine Concentration ◽  
Plasma Adma ◽  
End Stage ◽  
Adma Concentration

Objectives: we aimed to assess the levels of plasma ADMA in healthy people and in reserved patients with end stage renal disease (ESRD), the association between plasma ADMA with serum creatinine concentration and with eGFR. Materials and Methods: This is a controlled cross sectional study. Plasma ADMA and other variables were measured in 27 patients with ESRD and in 21 controls. Plasma ADMA levels were determined by enzyme linked immunosorbent assay (ELISA) using kits provided from immunodiagnostic AG, Germany. Data was analyzed by SPSS 19.0. Results: Mean ADMA in men- women was 0.69 ± 0.19 µmol/L and 0.61 ± 0.20 µmol/L, respectively, (p>0.05), mean ADMA in control and disease were 0.48 ± 0.17 µmol/L and 0.77± 0.12µmol/L; respectively, (p <0.001). No correlation between ADMA and age (r=-0.059, p=0.691); correlation between ADMA with serum creatinine (r=0.459, p<0.001) with eGFR r=-0.596, p<0.001). Conclusion: ADMA concentration in healthy people: 0.48 ± 0.17 µmol/L. ADMA concentration in ESRD: 0.77± 0.12 µmol/L. There is a correlation between ADMA concentration with eGFR and with serum creatinine concentration. Key words: Asymmetric dimethylarginine, end stage chronic kidney disease

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