Plasma Endothelin-1 Concentrations Research Articles

Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials.

Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations. The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD:-0.30pg/mL, 95%CI:-0.47,-0.13; p<0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD:-0.51pg/mL, 95%CI:-0.89,-0.14, p<0.01; >12 week -WMD:-0.19pg/mL, 95%CI:-0.36,-0.02; p<0.05) or by dose of statins (<40mg/day - WMD:-0.27pg/mL, 95%CI:-0.49,-0.05; p=0.01; >40mg/day - WMD:-0.38pg/mL, 95%CI:-0.68,-0.08; p=0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD:-0.34pg/mL, 95%CI:-0.55,-0.13; p<0.01), but not a hydrophilic statin (pravastatin - WMD:-0.18pg/mL, 95%CI:-0.44-0.08; p>0.05) had a significant effect in promoting ET-1 reduction. Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.

Abstract 479: Orotic Acid Induces Hypertension Associated With Impaired Endothelial Nitric Oxide Synthesis

Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVEC). A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMPK/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.

Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) is caused by mutations in the NKTR1 gene. This affects the development of nerve growth factor (NGF)-dependent neurons including sympathetic cholinergic neurons in the skin, causing anhidrosis. Cardiovascular and blood pressure regulation appears normal, but the integrity of sympathetic adrenergic neurons has not been tested. We examined the effect of posture on blood pressure, heart rate, plasma concentration of catecholamines, vasopressin, endothelin, and renin activity in 14 patients with CIPA, 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls. In all 14 patients with CIPA, plasma norepinephrine levels were very low or undetectable and failed to increase when the patient was upright, yet upright blood pressure was well maintained. Plasma epinephrine levels were normal and increased when the patient was upright. Plasma renin activity also increased appropriately when the patient was upright and after furosemide-induced volume depletion. Nitric oxide-mediated endothelial function was intact. Patients with pure autonomic failure also had very low levels of plasma norepinephrine both supine and upright, but in contrast to patients with CIPA failed to maintain blood pressure upright. The results indicate that postganglionic sympathetic neurons are severely depleted in CIPA, but chromaffin cells of the adrenal medulla are spared. This confirms the differential effect of NGF signaling for sympathetic neural and chromaffin cell development. The finding that patients with CIPA maintain blood pressure well on standing challenges current concepts of the role of norepinephrine in the regulation of arterial pressure.

Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru.

Painschab, Matthew S., Gary E. Malpartida, Victor G. Davila-Roman, Robert H. Gilman, Todd M. Kolb, Fabiola Leon-Velarde, J. Jaime Miranda, and William Checkley. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. High Alt Med Biol 16:26-33, 2015.-Long-term residence at high altitude is associated with the development of chronic mountain sickness (CMS), which is characterized by excessive erythrocytosis (EE). EE occurs under chronic hypoxia, and a strongly selected mutation in hypoxia-inducible factor 2α (HIF2A) has been found in native Tibetans that correlates with having a normal hemoglobin at high altitude. We sought to evaluate differences in plasma levels of four HIF-responsive proteins in 20 participants with EE (hemoglobin >21 g/dL in men and >19 in women) and in 20 healthy, age- and sex-matched participants without EE living at high altitude in Puno, Peru. We performed ELISA to measure plasma levels of the four HIF-responsive proteins: vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin. As a secondary aim, we evaluated the association between HIF-responsive proteins and echocardiography-estimated pulmonary artery systolic pressure (PASP) in a subset of 26 participants. sVEGF-R1 was higher in participants with vs. without EE (mean 107 pg/mL vs. 90 pg/mL; p=0.007). Although plasma concentrations of endothelin-1, VEGF, and erythropoietin were higher in participants with vs. without EE, they did not achieve statistical significance (all p>0.25). Both sVEGF-R1 (p=0.04) and erythropoietin (p=0.04) were positively associated with PASP after adjustment for age, sex, and BMI. HIF-responsive proteins may play a pathophysiological role in altitude-related, chronic diseases but our results did not show consistent changes in all measured HIF-responsive proteins. Larger studies are needed to evaluate for additional genetic and environmental risk factors.

Plasma endothelin-1 level, measured glomerular filtration rate and effective renal plasma flow in diabetic nephropathy

Background: Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy. Methods: We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m2; n = 50), group II (GFR ≥ 60 mL/min/1.73 m2, n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured. Results: There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = −0.52, p < 0.001), ERPF (r = −0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR. Conclusion: A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.

Nicorandil improves myocardial function by regulating plasma nitric oxide and endothelin-1 in coronary slow flow.

BackgroundCoronary slow flow (CSF) is a special coronary microvascular disorder. The pathogenesis and effective therapeutics of CSF remain unclear. This study aimed to evaluate the global and regional functions of the left ventricle (LV) and investigate the efficacy of nicorandil in patients with CSF.Patients and methodsThirty-six patients with CSF in the left anterior descending (LAD) branch and 20 patients with normal coronary arteries were included. Global and regional functions of the LV supplied by LAD were measured using conventional Doppler echocardiography and two-dimensional speckle tracking echocardiography, respectively, within 24 h after coronary angiography. Concentrations of plasma nitric oxide (NO) and endothelin-1 (ET-1) were detected using colorimetry and radioimmunoassay, respectively. The function of the LV and the levels of NO and ET-1 were also investigated before and 90 days after treatment with 15 mg/day of nicorandil.ResultsCompared with the control group, the early diastolic peak velocity (E), E/A ratio, and plasma NO levels were lower, whereas the late diastolic peak flow velocity (A) and plasma ET-1 levels were significantly higher in the CSF group (P<0.05). The longitudinal strain rate peak of the LV was reduced significantly in CSF patients (P<0.001). After treatment, 75% (27/36) of CSF patients were free of chest pain. The values of E peak, E/A ratio, longitudinal strain rate peak, and plasma NO level were increased (P<0.001), whereas the ET-1 level was decreased in CSF patients (P<0.001).ConclusionNicorandil may improve chest pain symptoms and the impaired function of the LV, possibly by increasing plasma NO and reducing ET-1 in CSF.

Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis.

Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells. A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMP-activated protein kinase/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.

Curcumin and major depression: A randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change

A recent randomised, double-blind, placebo controlled study conducted by our research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p<0.05), and substance P (p<0.001); while placebo supplementation was associated with reductions in aldosterone (p<0.05) and cortisol (p<0.05). Higher baseline plasma endothelin-1 (rs=−0.587; p<0.01) and leptin (rs=−0.470; p<0.05) in curcumin-treated individuals was associated with greater reductions in IDS-SR30 score after 8 weeks of treatment. Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action. Plasma concentrations of leptin and endothelin-1 seem to have particular relevance to treatment outcome. Further investigations using larger samples sizes are required to elucidate these findings, as the multiple statistical comparisons completed in this study increased the risk of type I errors.

Exercise in a hot environment influences plasma anti-inflammatory and antioxidant status in well-trained athletes

Exercise in thermally stressful environmental conditions can enhance oxidative stress. We sought to measure the plasma antioxidant defenses and cytokine response together with oxidative damage post-exercise in a temperate versus a hot environment. The plasma concentrations of vasoactive endothelin-1 and vascular angiogenic growth factor were also evaluated. Male athletes (n=9) volunteered to participate. The athletes randomly performed two bouts of treadmill exercise of 45min at 75–80% of maximal oxygen uptake in a climatic-controlled chamber under two different conditions: temperate environment (10–12°C, 40–55% humidity) and hot, humid environment (30–32°C, 75–78% humidity). Venous blood samples were obtained immediately pre- and post-bout and on recovery after 2h. Serum glucose, malondialdehyde and lactate concentrations were significantly increased post-exercise in hot but maintained in the temperate environment; these post-exercise values were significantly higher after exercise in hot than in temperate. Urinary 8-hydroxy-2′-deoxyguanosine concentration, plasma phosphocreatine kinase and catalase activities, creatinine and monocyte chemoattractant protein-1, and interleukin-6 significantly increased post-exercise in hot but maintained in temperate environment. The post-exercise circulating values of antioxidant enzyme paraoxonase-1 and endothelin were significantly higher in the hot than in temperate environment. Exercise in a hot and humid environment resulted in mild hyperthermia with elevated perceived exertion and thermal stress. Hyperthermic environment induced hyperglycemia, lactatecidemia and more cellular and oxidative damage than exercise in a temperate environment but also induced a post-exercise antioxidant and anti-inflammatory response in plasma. These results suggest that environmental temperature needs to be taken into account when evaluating exercise-related oxidative stress and inflammation.

Effects of pulse-delivered inhaled nitric oxide administration on pulmonary perfusion and arterial oxygenation in dorsally recumbent isoflurane-anesthetized horses.

To image the spatial distribution of pulmonary blood flow by means of scintigraphy, evaluate ventilation-perfusion (VA/Q) matching and pulmonary blood shunting (Qs/Qt) by means of the multiple inert gas elimination technique (MIGET), and measure arterial oxygenation and plasma endothelin-1 concentrations before, during, and after pulse-delivered inhaled nitric oxide (PiNO) administration to isoflurane-anesthetized horses in dorsal recumbency. 3 healthy adult Standardbreds. Nitric oxide was pulsed into the inspired gases in dorsally recumbent isoflurane-anesthetized horses. Assessment of VA/Q matching, Qs/Qt, and Pao2 content was performed by use of the MIGET, and spatial distribution of pulmonary blood flow was measured by perfusion scintigraphy following IV injection of technetium Tc 99m-labeled macroaggregated human albumin before, during, and 30 minutes after cessation of PiNO administration. During PiNO administration, significant redistribution of blood flow from the dependent regions to the nondependent regions of the lungs was found and was reflected by improvements in VA/Q matching, decreases in Qs/Qt, and increases in Pao2 content, all of which reverted to baseline values at 30 minutes after PiNO administration. Administration of PiNO in anesthetized dorsally recumbent horses resulted in redistribution of pulmonary blood flow from dependent atelectatic lung regions to nondependent aerated lung regions. Because hypoxemia is commonly the result of atelectasis in anesthetized dorsally recumbent horses, the addition of nitric oxide to inhaled gases could be used clinically to alleviate hypoxemia in horses during anesthesia.

Inappropriately elevated endothelin‐1 plays a role in the pathogenesis of intradialytic hypertension

The aim of this study is to investigate the effects of endogenous vasoactive substances on the occurrence of intradialytic hypertension (IDH) in patients during maintenance hemodialysis. Thirty-four maintenance hemodialysis patients were enrolled in this trial, and 17 of them were diagnosed with IDH (defined as an increase in blood pressure of at least 10 mmHg during or immediately after a hemodialysis session), while 17 age-matched and sex-matched controls without IDH were selected for a retrospective comparison. We collected patients' blood samples before and after a dialysis session and measured the plasma levels of N-terminal fragment brain natriuretic peptide, renin, angiotensin-II, aldosterone (ALD), angiotensin-converting enzyme (ACE), endothelin-1 (ET-1), nitric oxide (NO), norepinephrine (NOR), and adrenomedullin. The post-dialysis serum ET-1 concentrations were significantly higher (4.09 ± 2.06 vs. 2.75 ± 1.34 pg/mL, P < 0.05), while the post-dialysis ratio of NO to ET-1 was lower (17.79 ± 5.65 vs. 24.78 ± 12.04, P < 0.05) in IDH patients compared with the control group. Post-dialysis ALD and NOR values were significantly lower (P < 0.01) and ACE levels were significantly higher (P < 0.01) than the pre-dialysis concentrations only in the control and not in the IDH group. All other measured factors did not differ significantly between the groups and between pre-dialysis and post-dialysis determinations. Compared with blood angiotensin-II, ALD, ACE, NOR, adrenomedullin, N-terminal fragment brain natriuretic peptide, and NO status, inappropriately elevated ET-1 plasma concentrations may play a predominant role in the pathogenesis of IDH.

Adrenergic and non-adrenergic control of active skeletal muscle blood flow: implications for blood pressure regulation during exercise.

Blood flow to active skeletal muscle increases markedly during dynamic exercise. However, despite the massive capacity of skeletal muscle vasculature to dilate, arterial blood pressure is well maintained. Sympathetic nerve activity is elevated with increased intensity of dynamic exercise, and is essential for redistribution of cardiac output to active skeletal muscle and maintenance of arterial blood pressure. In addition, aside from the sympathetic nervous system, evidence from human studies is now emerging that supports roles for non-adrenergic vasoconstrictor pathways that become active during exercise and contribute to vasoconstriction in active skeletal muscle. Neuropeptide Y and adenosine triphosphate are neurotransmitters that are co-released with norepinephrine from sympathetic nerve terminals capable of producing vasoconstriction. Likewise, plasma concentrations of arginine vasopressin, angiotensin II (Ang II) and endothelin-1 (ET-1) increase during dynamic exercise, particularly at higher intensities. Ang II and ET-1 have both been shown to be important vasoconstrictor pathways for restraint of blood flow in active skeletal muscle and the maintenance of arterial blood pressure during exercise. Indeed, although both adrenergic and non-adrenergic vasoconstriction can be attenuated in exercising muscle with greater intensity of exercise, with the higher volume of blood flow, the active skeletal muscle vasculature remains capable of contributing importantly to the maintenance of blood pressure. In this brief review we provide an update on skeletal muscle blood flow regulation during exercise with an emphasis on adrenergic and non-adrenergic vasoconstrictor pathways and their potential capacity to offset vasodilation and aid in the regulation of blood pressure.

Effect of atorvastatin on exercise tolerance in patients with diastolic dysfunction and exercise-induced hypertension

To investigate the effect of atorvastatin on exercise tolerance in patients with diastolic dysfunction and exercise-induced hypertension. A randomized, double-blind, placebo-controlled prospective study was performed. Sixty patients with diastolic dysfunction (mitral flow velocity E/A <1) and exercise-induced hypertension (SBP>200 mm Hg) treated with atorvastatin (20 mg q.d) or placebo for 1 year. Cardiopulmonary exercise test and exercise blood pressure measurement were performed. Plasma B-natriuretic peptide (BNP) concentration at rest and at peak exercise, plasma high sensitive-C reaction protein (hs-CRP) and endothelin (ET) concentration were determined at baseline and after treatment. After treatment by atorvastatin, the resting SBP, pulse pressure, the peak exercise SBP and BNP were significantly decreased; and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were increased. All of these parameters had significant differences with baseline levels (P<0.05) and the rest pulse pressure, the peak exercise SBP and BNP, and the exercise time had significant differences compared with placebo treatment (P<0.05). Plasma concentrations of hs-CRP and ET were markedly reduced by atorvastatin treatment compared with baseline and placebo (P<0.05). No difference in above parameters was found before and after placebo treatment (P>0.05). In patients with diastolic dysfunction at rest and exercise-induced hypertension, atorvastatin can effectively reduce plasma hs-CRP and ET level, lower blood pressure and peak exercise SBP, decrease peak exercise plasma BNP concentration, and ultimately improve exercise tolerance.

Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children

AimsThis study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children. Materials and methodsThirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A] and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay. Key findingsPlasma ET-1 concentrations were higher in NS patients (P=0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P=0.057). Plasma cholesterol in NS patients is associated with both: the GT genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P<0.05 in both cases). SignificanceThe ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS, seems to be associated with genetic variations within the human ET-1 gene.

Analysis of Long-term Stored Plasma Samples for Investigation into the Pathophysiology of Vibration-induced White Finger: Preliminary Results

Blood samples were collected 25 yr ago from hand-arm vibration syndrome patients with vibration-induced white finge/VWF (VWF+ group) and without it (VWF− group), and healthy controls (n=12 in each group), and stored at −80°C. The subjects provided venous blood twice: at baseline, and after cold exposure at 7°C for 25 min. Blood specimens were analyzed for plasma endothelin-1 (ET-1) by an enzyme-linked immunosorbent assay. Baseline concentration of plasma ET-1 was found to be significantly larger in the VWF– group than the control group, whereas no such difference was observed for the VWF+ group. However, the %change was larger in the VWF+ group (107.73 ± 30.49%) than the other two groups, and more subjects in the VWF+ group showed the maximum increase in ET-1 than the other two groups. In conclusion, ET-1 appears to have a role in the pathophysiology of VWF.

Bosentan reduces neuronal apoptosis following spinal cord ischemic reperfusion injury

Experimental study. To investigate the effects of endothelin-receptor antagonist Bosentan on the spinal neural apoptosis in rats with ischemic reperfusion (IR) injury. Department of Neurosurgery, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medcine, Xi'an, Shaanxi Province, China: Sprague-Dawley Rats were randomly divided into two groups, saline (IRS, n=48) and Bosentan (IRB, n=48) treatment, respectively, when reperfused in 6 h, 12 h, 24 h, 3 days, 5 days and 7 days. Immunohistochemical staining was used to assess endothelin-1 (ET-1), endothelin receptor type A (ETRA), endothelin receptor type B (ETRB), Bcl-2, Bax, Caspase-8, Caspase-9 and Caspase-3 expression. ET-1 and its receptor in spinal cord tissue were evaluated by real-time PCR. Plasma ET-1 concentration was also detected using radioimmunoassay. Compared with the group IRS, plasma concentration of ET-1 in group IRB was significantly increased at each time point (P<0.05) and peaked at 24 h (P<0.01). ETRB expression in group IRB was significantly higher than group IRS at each time point (P<0.05) and peaked at day 3 (P<0.01). The difference in the expression of ETRA was not statistically significant in the group IRS and IRB (P>0.05). The apoptosis rate in group IRB was significantly decreased at each time point (P<0.05). The protein expressions of Bcl-2, Bax, Caspase-8, Caspase-9 and Caspase-3 were significantly increased in response to Bosentan treatment after IR. These results suggest Bosentan decreases apoptosis rate after IR injury in the spinal cord, possibly through the ET-1-ETRB signaling pathway.

Effects of the rate of insulin infusion during isoglycemic, hyperinsulinemic clamp procedures on measures of insulin action in healthy, mature thoroughbred mares

The objective of this study was to determine whether the rate of insulin infusion during isoglycemic hyperinsulinemic clamp procedures affected measures of insulin action, including glucose disposal and plasma non-esterified fatty acid, endothelin-1, and nitric oxide concentrations, in mature, healthy horses. Eight thoroughbred mares were studied during a 2-h hyperinsulinemic clamp procedure, conducted at each of 4 rates of insulin infusion: 0 (CON), 1.2 (LOWINS), 3 (MEDINS), and 6 (HIGHINS) mU·kg−1·min−1. The infusion rate of a dextrose solution was adjusted throughout the clamp procedures to maintain blood glucose levels within 10% of baseline glucose concentrations. Plasma insulin concentrations were measured throughout the clamp procedures, and used with the rate of glucose infusion to calculate the plasma insulin concentration-to-rate of glucose infusion ratio, a measure of insulin action on glucose disposal. The rate of glucose infusion increased with rate of insulin infusion (P < 0.05). The plasma insulin concentration-to-rate of glucose infusion ratio was highest for the LOWINS treatment (P < 0.05) and decreased by 62% (P < 0.05) and 84% (P < 0.05) for the MEDINS and HIGHINS treatments, respectively. Although plasma non-esterified fatty acid concentrations were lower than baseline by t = 30 min of the clamp procedures in the LOWINS, MEDINS, and HIGHINS treatments (P < 0.05), the decline was similar for all 3 rates of insulin infusion. Jugular vein plasma nitric oxide and endothelin-1 concentrations were not affected by insulin infusion rate (P > 0.05). The data indicate that it is important to standardize insulin infusion rate if data are to be compared between hyperinsulinemic clamp studies.

Oxygenation and plasma endothelin‐1 concentrations in healthy horses recovering from isoflurane anaesthesia administered with or without pulse‐delivered inhaled nitric oxide: Oxygenation & ET‐1 in horses after isoflurane & iNO

ObjectiveTo assess oxygenation, ventilation‐perfusion (V/Q) matching and plasma endothelin (ET‐1) concentrations in healthy horses recovering from isoflurane anaesthesia administered with or without pulse‐delivered inhaled nitric oxide (iNO). Study DesignProspective experimental trial. AnimalsHealthy adult Standardbred horses. MethodsHorses were anaesthetized with isoflurane in oxygen and placed in lateral recumbency. Six control (C group) horses were anaesthetized without iNO delivery and six horses received pulse‐delivered iNO (NO group). After 2.5 hours of anaesthesia isoflurane and iNO were abruptly discontinued, inhaled oxygen was reduced from 100% to approximately 30%, and the horses were moved to the recovery stall. At intervals during a 30‐minute period following the discontinuation of anaesthesia, arterial and mixed venous blood gas values, shunt fraction (Qs/Qt), plasma ET‐1 concentration, pulse rate and respiratory rate were measured or calculated. Repeated measures anova and a Bonferroni post hoc test was used to analyze data with significance set at p < 0.05. ResultsAt all time points in the recovery period, NO horses maintained better arterial oxygenation (oxygen partial pressure: NO 13.2 ± 2.7–11.1 ± 2.7 versus C 6.7 ± 1.1–7.1 ± 1.1 kPa) and better V/Q matching (Qs/Qt NO 0.23 ± 0.05–0.14 ± 0.06 versus C 0.48 ± 0.03–0.32 ± 0.08%) than C horses. Mixed venous oxygenation was higher in NO for 25 minutes following the discontinuation of anaesthesia (NO 6.3 ± 0.2–4.5 ± 0.07 versus C 4.7 ± 0.6–3.7 ± 0.3 kPa). In both groups of horses arterial oxygenation remained fairly stable; venous oxygenation declined over this time period in the NO group but still remained higher than venous oxygen in the C group. ET‐1 concentrations were higher at most time points in C than NO. Changes in other parameters were either minor or absent. Conclusions and Clinical RelevanceDelivery of iNO to healthy horses during anaesthesia results in better arterial and venous oxygenation and V/Q matching (as determined by lower Qs/Qt) and lower ET‐1 concentrations throughout a 30‐minute anaesthetic recovery period.

Plasma Endothelin-1 as Screening Marker for Cerebral Vasospasm After Subarachnoid Hemorrhage

Cerebral vasospasm complicating subarachnoid hemorrhage causes ischemic stroke and worsens the neurological outcome. The potential role of endothelin-1 in vasospasm pathogenesis may provide therapeutic opportunities. A recent meta-analysis however, did not support the use of endothelin antagonists. Apart from clinical assessment, transcranial Doppler and interval angiography, there are no sensitive screening markers for evolving vasospasm. We investigate the ability of serial measurement of endothelin-1 to predict the development of vasospasm following subarachnoid hemorrhage. Endothelin-1 levels in cerebrospinal fluid and blood were measured daily in 20 patients admitted to the ICU with subarachnoid hemorrhage from days 1 to 10 following the inception bleed. In addition to clinical assessment, patients had daily transcranial Doppler. Digital subtraction angiography was performed on the suspicion of vasospasm based upon clinical or transcranial Doppler assessment. Neuron-specific enolase and SB100 were measured in blood as comparative biomarkers of neurological injury. Mean plasma endothelin-1 on day 5, was 4.2 mcg/L (CI 3.1-5.8) in patients with vasospasm compared to 2.5 mcg/L (CI 1.5-4.0) in those without vasospasm (P = 0.047). There were no time-related differences in cerebrospinal fluid endothelin-1, plasma NSE, or SB100 for patients with and without vasospasm. In patients with subarachnoid hemorrhage and vasospasm, endothelin-1 is significantly higher in plasma than in CSF on day 5. Neither NSE nor SB100 is associated with the development of vasospasm. Measurement of serial plasma endothelin-1 concentration is a potential screening marker of vasospasm.

GW24-e0023 Endothelial function and carotid IMT deteriorated in Tibetan adolescents exposed to second-hand smoke

ObjectivesTo investigate the endothelial function and carotid atherosclerosis in healthy school-aged Tibetan male adolescents.MethodsAll participants with SHS were recruited through middle-school students with 16-year-old and male gender in Lhasa city....