BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel ...BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel and beneficial drug for DN,no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIM To assess the effectiveness and safety of ER antagonists among patients with DN.METHODS The EMBASE,PubMed,MEDLINE,Cochrane,and ClinicalTrials.gov databases were searched without any language restrictions.Relative risks with 95%confidence intervals(CIs)for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software.Publication bias was assessed using Egger’s test with Stata/SE software.RESULTS We enrolled seven studies with six data sets and 5271 participants.The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40%reduction in urinary albumin-to-creatinine ratio than the control group(P<0.0001 and P=0.02,respectively).Subgroup analysis for reductions in estimated glomerular filtration rate(eGFR)showed that for the middle-dosage subgroup,the ER antagonists group exhibited lower eGFR reduction than the control group(P<0.00001;mean difference,0.7095%CI:0.66,0.74).Moreover,significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor/angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR.However,attention should be given to adverse events,including cardiac failure,anemia,and hypoglycemia,as well as serious adverse events.展开更多
To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia1...To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia11y reported by various authors. We have performed investigations in anesthetized Sprague-Dawley rats- Intracisternal injection (i. c. ) of ET-l (10-11, 10-10, 10-9 mol/kg) could induce acute dose-dependent CVS, furthermore, the highest dose of ET-l (lO-’ mo1/kg) had a biphasic response in CVS of a 24-hour duration. However, the CVS by ET-1 (10-9 mol/kg) could be prevented effectively by previous i. c. of BQ-123 in a dose-dependent manner (10-9, 10-8, 10-7 mol/kg), of which the i. c- of BQ-123 (10-7mol/kg) could abolish the CVS completely. i. c. of BQ-123 (10-7 mol/kg) before SAH induced by a single i. c, of 150 pl autologous fresh blood directly to the Willis circle cou1d prevent the following CVS largely, which was a biphasic response and long-lasting (duration of 72 h). We conclude that subarachnoid application of ETA-receptor antagonist can effecti vely prevent CVS induced by ET-1 and SAH, and ET-1 may be the major mediator responsible for the CVS following SAH.展开更多
Objective: To explore the changes of plasma endothelin(ET) and nitric oxide (NO) levels in patients with a-cute pancreatitis.Methods: The level of plasma ET was measured by ra-dioactive-immunoassay, and NO by spectrop...Objective: To explore the changes of plasma endothelin(ET) and nitric oxide (NO) levels in patients with a-cute pancreatitis.Methods: The level of plasma ET was measured by ra-dioactive-immunoassay, and NO by spectrophotometry.Results: The levels of ET, NO and the ET/NO ratioin patients with severe acute pancreatitis(SAP) within24 hours in hospital were all significantly higher thanthose in other groups of patients [(176±8)pg/ml,(97±11) μmol/L, and 1.83±0.12, P【0.01]. Com-pared to healthy controls(N), the levels of ET and NOin patients without pancreatitis acute abdomen (NAP)and patients with mild acute pancreatitis (MAP) in-creased significantly (P【0.01). After appropriate treat-ment, the levels of ET and NO in the MAP groupwere lower (P【0.01). Compared with those beforetreatment, the levels of ET and NO in the SAP groupon the 3rd and 7th day in hospital dropped signifi-cantly(P【0.01).The ET/NO ratio on the 7th daywas also lower than that on admission (P【0.01).Conclusions: The malfunction of endothelial cells andthe increased ET/NO ratio may be related to the mecha-nism of pancreatic microcirculatory disturbance in pa-tients with SAP; early dynamic determination of theseparameters may help predict the prognosis of SAP.展开更多
INTRODUCTIONEndothelins(ETs) has a potent and sustainedvasoconstrictive effect on a variety of blood vessels.The vascular smooth muscle cell (VSMC)is thetarget for ETs.VSMC of the whole body containsendothelin recepto...INTRODUCTIONEndothelins(ETs) has a potent and sustainedvasoconstrictive effect on a variety of blood vessels.The vascular smooth muscle cell (VSMC)is thetarget for ETs.VSMC of the whole body containsendothelin receptor (ETR).A great number ofexperiments have shown that three distinctcomplementary DNAs of ETR have been identifiedi.e.,endothelin A receptor(ET_A receptor),endothelin B receptor(ET_B receptor)展开更多
AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP...AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot. RESULTS: PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31+ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA+ smooth muscle cells of arterioles and in the CD31+ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2. CONCLUSION: Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.展开更多
INTRODUCTIONPortal hypertension is a common clinical syndromecharacterized by an abnormal increase in portalblood to the systemic circulation, bypassing theliver. Recent studies have reported that humoralsubstances pl...INTRODUCTIONPortal hypertension is a common clinical syndromecharacterized by an abnormal increase in portalblood to the systemic circulation, bypassing theliver. Recent studies have reported that humoralsubstances play an important role in thepathogenesis of portal hypertension, either byincreasing vascular resistance at both theintrahepatic and porto-collateral sites or affectingsplanchnic vasodilation with a concomitant increasein parto-collateral blood flow[1-6]展开更多
BACKGROUND: Melatonin exerts complex physiological and pharmacological effects on multiple systems and organs. We hypothesized that melatonin might abate ischemia/ reperfusion (I/R) injury in the liver by inhibiting e...BACKGROUND: Melatonin exerts complex physiological and pharmacological effects on multiple systems and organs. We hypothesized that melatonin might abate ischemia/ reperfusion (I/R) injury in the liver by inhibiting excessive oxidative stress and keeping nitric oxide (NO) from being scavenged by free radicals. The aim of the present study was to investigate whether melatonin protects the liver from I/R injury and, if so, by what underlying mechanism. METHODS: Under anesthesia, Wistar rats were intraperi- toneally injected with 20 mg/kg melatonin (dissolved in physiological saline containing 4% ethanol, Mel group), 4% alcohol (Alc group), or physiological saline (NS group). The artery, portal vein and bile duct of the left lobe of the liver were clamped for 60 minutes and then released. At different time points after I/R, the rats were sacrificed and blood samples were collected to measure the levels of serum alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and NO. Hepatic tissue samples were collected for measuring endothelin expression by immunohistochemical staining and for routine morphological and histological examination. RESULTS: The levels of both ALT and LDH in the Mel group were significantly reduced for up to 24 hours after I/R compared with the Alc and NS groups (P<0.05). The levels of NO in the Mel group were significantly elevated for up to 12 hours after I/R relative to the NS group (P<0.05). The NO levels were also elevated at 0.5 and 6 hours after I/R in the Alc group (P<0.05). The immunohistochemical staining of hepatic tissue showedthat endothelin-positive cells were significantly fewer in the Mel group than in the Alc and NS groups at 6 hours after I/R (P<0.01). The necrosis of hepatocytes and the destruction of hepatic cords in the Alc and NS groups were greatly improved in Mel-treated rats, which is in concert with our functional data. CONCLUSIONS: Pretreatment with melatonin increased NO bioavailability and decreased endothelin expression, and consequently played a protective role in preserving both liver function and structure during ischemia and reperfusion injury.展开更多
BACKGROUND:Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT).Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT.The study ...BACKGROUND:Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT).Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT.The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome.METHODS:Fifty-seven cirrhotic patients [43 males;median age 58 (28-87) years] underwent Doppler echocardiography.Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT.ET-1,2,and 3 serum levels were measured with an ELISA assay.All-cause mortality was recorded over a median period of 24 months.RESULTS:Nine out of 57 patients (15.8%) had PPHT.Among various clinical variables,only autoimmune hepatitis was associated with PPHT (OR=11.5;95% CI,1.58-83.4;P=0.01).ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL,P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7),P=0.02] were significantly higher in patients with PPHT than in those without.ET-2 and ET-3 levels did not differ between the two groups.There was no difference in survival between the two groups,although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11;95% CI,1.02-1.22;P=0.02 per unit increase in ET-1).CONCLUSION:Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.展开更多
BACKGROUND: Acute pancreatitis remains a common presentation to acute surgical units and carries significant morbidity and mortality. The progression of the disease to necrotizing pancreatitis and multi-organ dysfunct...BACKGROUND: Acute pancreatitis remains a common presentation to acute surgical units and carries significant morbidity and mortality. The progression of the disease to necrotizing pancreatitis and multi-organ dysfunction syndrome (MODS) is associated with a very poor clinical outcome, and persistendy high mortality. Increases in serum endothelin (ET) have been seen in animal models of acute pancreatitis and this study aims to investigate whether there is a change in serum ET-1 in patients with acute pancreatitis and whether any such change is linked to disease severity. METHODS: All patients admitted with acute pancreatitis were prospectively recruited from die emergency admissions at the Norfolk and Norwich University Hospital. Serum ET levels were determined on admission, at 24 hours and 5 days post admission. Healthy adult controls were recruited from dermatology outpatients. RESULTS: A total of 21 patients joined the trial after giving informed consent. There were 3 men and 18 women with a median age of 65 years (range 26-87 years). Serum ET levels were significantly higher in acute pancreatitis patients than in normal controls (P 【0. 05). An association was seen between persistendy raised serum ET levels and progression to MODS. CONCLUSIONS: The study does demonstrate a correlation between the circulating levels of ET and acute pancreatitis in humans, although it does not elicit its involvement in the pathogenesis of the disease. The observation that a persistendy high level of circulating ET-1 is associated with progression to MODS may indicate a role for ET in the monitoring of acute pancreatitis patients for recovery or progression to MODS.展开更多
The effect of astragalus on the endothelin in serum and lung of the rats with acute lung injury was studied. The results demonstrated that the concentration of endothelin in the lung of the rats in therapy group was l...The effect of astragalus on the endothelin in serum and lung of the rats with acute lung injury was studied. The results demonstrated that the concentration of endothelin in the lung of the rats in therapy group was lower than that of the injured rats (64.36±5.37 ng/L vs 103.32±4.99 ng/L, P <0.001), and level of serum endothelin was also lower than that of the injured rats (85.35 ng/L vs 113.35 ng/L, P <0.01). PaO 2, serum SOD, lung coefficient, ratio of lung wet weight/dry weight in two groups were also significantly different ( P <0.01) respectively, and the lung pathological injury in the treatment group were less than that of injury group. So it is concluded that astragalus could inhibit the increase of serum and lung endothelin, thereby playing a protective role in the rats with acute lung injury.展开更多
To investigate the effects of L-tetrahydropalmatine (L-THP) on ener-gy metabolism, endothelin-1 (ET-1 ) and NO during acute cerebral ischemia-reperfusion of rats, 24 Wistar rats were randomly divided into four groups,...To investigate the effects of L-tetrahydropalmatine (L-THP) on ener-gy metabolism, endothelin-1 (ET-1 ) and NO during acute cerebral ischemia-reperfusion of rats, 24 Wistar rats were randomly divided into four groups, with 6rats in each group: sham-operation group, simple ischemia group, ischemia-reperfusion group and treatment group (L-THP group). Cerebral ATP, lactate,ET-1 and NO levels were measured in all groups. Our results showed that treat-ment with L-THP could increase cerebral ATP levels, but decrease cerebral lac-tate, ET-1 and NO concentrations during ischemia-reperfusion in the treatmentgroup. It is concluded that L-THP could improve cerebral energy metabolism and protect the injured brain tissue, the mechanism of which might be related to suppression of overproduction of ET-1 and NO.展开更多
The purpose of the present study was to assess the correlation that likely exists among increased portal pressure (P p), portal blood flow quantity (Q p) and ET A and ET B receptor mRNA expression in human cirrhosis. ...The purpose of the present study was to assess the correlation that likely exists among increased portal pressure (P p), portal blood flow quantity (Q p) and ET A and ET B receptor mRNA expression in human cirrhosis. In situ hybridization and reverse transcription polymerase chain reactions (RT PCR) were performed to determine the expression of ET A and ET B receptor mRNA in liver tissues from traumatic subjects ( n =10) and cirrhotic patients ( n =15) in whom hepatic hemodynamic values were measured. The expression of the two transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from traumatic subjects. It has shown that ET A receptor mRNA predominantly located in hepatic stellate cells (HSCs) and vascular smooth muscle cells of intrahepatic arteries and portal veins, ET B receptor mRNA in HSCs, sinusoidal endothelial cells and Kuppfer cells. There was a highly significant direct relationship between ET A and ET B receptor mRNA and P p and Q p in cirrhotic patients. It suggests that liver paracrine endothelin system may be overactivated in human cirrhosis accompanied with increased expression of ET A and ET B receptor mRNA which may play an important role in the pathogenesis and maintenance of splanchnic hyperdynamics.展开更多
AIM:To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.METHODS:Wild type,e NOS-/-and i NOS-/-mice receivedpartial portal vein ligation surger...AIM:To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.METHODS:Wild type,e NOS-/-and i NOS-/-mice receivedpartial portal vein ligation surgery to induce portal hypertension or sham surgery.Development of portal hypertension was determined by measuring the splenic pulp pressure,abdominal aortic flow and portal systemic shunting.To measure splenic pulp pressure,a microtip pressure transducer was inserted into the spleen pulp.Abdominal aortic flow was measured by placing an ultrasonic Doppler flow probe around the abdominal aorta between the diaphragm and celiac artery.Portal systemic shunting was calculated by injection of fluorescent microspheres in to the splenic vein and determining the percentage accumulation of spheres in liver and pulmonary beds.Endothelin-1 hypo-response was evaluated by measuring the change in abdominal aortic flow in response to endothelin-1 intravenous administration.In addition,thoracic aorta endothelin-1contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph.RESULTS:In wild type and i NOS-/-mice splenic pulp pressure increased from 7.5±1.1 mm Hg and 7.2±1 mm Hg to 25.4±3.1 mm Hg and 22±4 mm Hg respectively.In e NOS-/-mice splenic pulp pressure was increased after 1 d(P=NS),after which it decreased and by 7 d was not significantly elevated when compared to 7 d sham operated controls(6.9±0.6 mm Hg and 7.3±0.8 mm Hg respectively,P=0.3).Abdominal aortic flow was increased by 80%and 73%in 7 d portal vein ligated wild type and i NOS when compared to shams,whereas there was no significant difference in 7 d portal vein ligated e NOS-/-mice when compared to shams.Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type,e NOS-/-and i NOS-/-sham mice(50%±8%,73%±9%and 47%±9%respectively).Following portal vein ligation endothelin-1 reduction in blood flow was significantly diminished in each mouse group.Abdominal aortic flow was reduced by 19%±9%,32%±10%and 9%±9%in wild type,e NOS-/-and i NOS-/-mice respectively.CONCLUSION:Aberrant endothelin-1 response in murine portal hypertension is NOS isoform independent.Moreover,portal hypertension in the portal vein ligation model is independent of ET-1 function.展开更多
A microwave-assisted solid phase synthesis for endothelin 1 is presented.Reduced endothelin 1 was synthesized efficiently on Wang resin under microwave irradiation using Fmoc/tBu orthogonal protection strategy.The who...A microwave-assisted solid phase synthesis for endothelin 1 is presented.Reduced endothelin 1 was synthesized efficiently on Wang resin under microwave irradiation using Fmoc/tBu orthogonal protection strategy.The whole peptide was cleaved from the resin and two disulphide bridges were formed under air oxidation at room temperature.The purity and efficiency of synthesizing the peptide is much higher than other methods used before.展开更多
文摘BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel and beneficial drug for DN,no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIM To assess the effectiveness and safety of ER antagonists among patients with DN.METHODS The EMBASE,PubMed,MEDLINE,Cochrane,and ClinicalTrials.gov databases were searched without any language restrictions.Relative risks with 95%confidence intervals(CIs)for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software.Publication bias was assessed using Egger’s test with Stata/SE software.RESULTS We enrolled seven studies with six data sets and 5271 participants.The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40%reduction in urinary albumin-to-creatinine ratio than the control group(P<0.0001 and P=0.02,respectively).Subgroup analysis for reductions in estimated glomerular filtration rate(eGFR)showed that for the middle-dosage subgroup,the ER antagonists group exhibited lower eGFR reduction than the control group(P<0.00001;mean difference,0.7095%CI:0.66,0.74).Moreover,significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor/angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR.However,attention should be given to adverse events,including cardiac failure,anemia,and hypoglycemia,as well as serious adverse events.
文摘To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia11y reported by various authors. We have performed investigations in anesthetized Sprague-Dawley rats- Intracisternal injection (i. c. ) of ET-l (10-11, 10-10, 10-9 mol/kg) could induce acute dose-dependent CVS, furthermore, the highest dose of ET-l (lO-’ mo1/kg) had a biphasic response in CVS of a 24-hour duration. However, the CVS by ET-1 (10-9 mol/kg) could be prevented effectively by previous i. c. of BQ-123 in a dose-dependent manner (10-9, 10-8, 10-7 mol/kg), of which the i. c- of BQ-123 (10-7mol/kg) could abolish the CVS completely. i. c. of BQ-123 (10-7 mol/kg) before SAH induced by a single i. c, of 150 pl autologous fresh blood directly to the Willis circle cou1d prevent the following CVS largely, which was a biphasic response and long-lasting (duration of 72 h). We conclude that subarachnoid application of ETA-receptor antagonist can effecti vely prevent CVS induced by ET-1 and SAH, and ET-1 may be the major mediator responsible for the CVS following SAH.
文摘Objective: To explore the changes of plasma endothelin(ET) and nitric oxide (NO) levels in patients with a-cute pancreatitis.Methods: The level of plasma ET was measured by ra-dioactive-immunoassay, and NO by spectrophotometry.Results: The levels of ET, NO and the ET/NO ratioin patients with severe acute pancreatitis(SAP) within24 hours in hospital were all significantly higher thanthose in other groups of patients [(176±8)pg/ml,(97±11) μmol/L, and 1.83±0.12, P【0.01]. Com-pared to healthy controls(N), the levels of ET and NOin patients without pancreatitis acute abdomen (NAP)and patients with mild acute pancreatitis (MAP) in-creased significantly (P【0.01). After appropriate treat-ment, the levels of ET and NO in the MAP groupwere lower (P【0.01). Compared with those beforetreatment, the levels of ET and NO in the SAP groupon the 3rd and 7th day in hospital dropped signifi-cantly(P【0.01).The ET/NO ratio on the 7th daywas also lower than that on admission (P【0.01).Conclusions: The malfunction of endothelial cells andthe increased ET/NO ratio may be related to the mecha-nism of pancreatic microcirculatory disturbance in pa-tients with SAP; early dynamic determination of theseparameters may help predict the prognosis of SAP.
文摘INTRODUCTIONEndothelins(ETs) has a potent and sustainedvasoconstrictive effect on a variety of blood vessels.The vascular smooth muscle cell (VSMC)is thetarget for ETs.VSMC of the whole body containsendothelin receptor (ETR).A great number ofexperiments have shown that three distinctcomplementary DNAs of ETR have been identifiedi.e.,endothelin A receptor(ET_A receptor),endothelin B receptor(ET_B receptor)
基金Supported by Grant from National Key New Drug Creation Project of China, No. 2009ZX09102
文摘AIM: To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling. METHODS: PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot. RESULTS: PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31+ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA+ smooth muscle cells of arterioles and in the CD31+ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2. CONCLUSION: Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.
基金Project supported by the National Natural Science FoundationMinistry of Public Health of China, No. 37600481
文摘INTRODUCTIONPortal hypertension is a common clinical syndromecharacterized by an abnormal increase in portalblood to the systemic circulation, bypassing theliver. Recent studies have reported that humoralsubstances play an important role in thepathogenesis of portal hypertension, either byincreasing vascular resistance at both theintrahepatic and porto-collateral sites or affectingsplanchnic vasodilation with a concomitant increasein parto-collateral blood flow[1-6]
基金This study was supported by a grant from Nature Science Foundation of Liaoning Province of China (No. 20042064).
文摘BACKGROUND: Melatonin exerts complex physiological and pharmacological effects on multiple systems and organs. We hypothesized that melatonin might abate ischemia/ reperfusion (I/R) injury in the liver by inhibiting excessive oxidative stress and keeping nitric oxide (NO) from being scavenged by free radicals. The aim of the present study was to investigate whether melatonin protects the liver from I/R injury and, if so, by what underlying mechanism. METHODS: Under anesthesia, Wistar rats were intraperi- toneally injected with 20 mg/kg melatonin (dissolved in physiological saline containing 4% ethanol, Mel group), 4% alcohol (Alc group), or physiological saline (NS group). The artery, portal vein and bile duct of the left lobe of the liver were clamped for 60 minutes and then released. At different time points after I/R, the rats were sacrificed and blood samples were collected to measure the levels of serum alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and NO. Hepatic tissue samples were collected for measuring endothelin expression by immunohistochemical staining and for routine morphological and histological examination. RESULTS: The levels of both ALT and LDH in the Mel group were significantly reduced for up to 24 hours after I/R compared with the Alc and NS groups (P<0.05). The levels of NO in the Mel group were significantly elevated for up to 12 hours after I/R relative to the NS group (P<0.05). The NO levels were also elevated at 0.5 and 6 hours after I/R in the Alc group (P<0.05). The immunohistochemical staining of hepatic tissue showedthat endothelin-positive cells were significantly fewer in the Mel group than in the Alc and NS groups at 6 hours after I/R (P<0.01). The necrosis of hepatocytes and the destruction of hepatic cords in the Alc and NS groups were greatly improved in Mel-treated rats, which is in concert with our functional data. CONCLUSIONS: Pretreatment with melatonin increased NO bioavailability and decreased endothelin expression, and consequently played a protective role in preserving both liver function and structure during ischemia and reperfusion injury.
基金supported by a grant from the Special Account for Research Funds(ELKE)of the National and Kapodistrian University of Athens,Greece(7493)
文摘BACKGROUND:Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT).Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT.The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome.METHODS:Fifty-seven cirrhotic patients [43 males;median age 58 (28-87) years] underwent Doppler echocardiography.Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT.ET-1,2,and 3 serum levels were measured with an ELISA assay.All-cause mortality was recorded over a median period of 24 months.RESULTS:Nine out of 57 patients (15.8%) had PPHT.Among various clinical variables,only autoimmune hepatitis was associated with PPHT (OR=11.5;95% CI,1.58-83.4;P=0.01).ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL,P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7),P=0.02] were significantly higher in patients with PPHT than in those without.ET-2 and ET-3 levels did not differ between the two groups.There was no difference in survival between the two groups,although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11;95% CI,1.02-1.22;P=0.02 per unit increase in ET-1).CONCLUSION:Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.
基金GI Research fund, Department of Upper GI Surgery,Norfolk and Norwich University Hospital NHS Trust.
文摘BACKGROUND: Acute pancreatitis remains a common presentation to acute surgical units and carries significant morbidity and mortality. The progression of the disease to necrotizing pancreatitis and multi-organ dysfunction syndrome (MODS) is associated with a very poor clinical outcome, and persistendy high mortality. Increases in serum endothelin (ET) have been seen in animal models of acute pancreatitis and this study aims to investigate whether there is a change in serum ET-1 in patients with acute pancreatitis and whether any such change is linked to disease severity. METHODS: All patients admitted with acute pancreatitis were prospectively recruited from die emergency admissions at the Norfolk and Norwich University Hospital. Serum ET levels were determined on admission, at 24 hours and 5 days post admission. Healthy adult controls were recruited from dermatology outpatients. RESULTS: A total of 21 patients joined the trial after giving informed consent. There were 3 men and 18 women with a median age of 65 years (range 26-87 years). Serum ET levels were significantly higher in acute pancreatitis patients than in normal controls (P 【0. 05). An association was seen between persistendy raised serum ET levels and progression to MODS. CONCLUSIONS: The study does demonstrate a correlation between the circulating levels of ET and acute pancreatitis in humans, although it does not elicit its involvement in the pathogenesis of the disease. The observation that a persistendy high level of circulating ET-1 is associated with progression to MODS may indicate a role for ET in the monitoring of acute pancreatitis patients for recovery or progression to MODS.
文摘The effect of astragalus on the endothelin in serum and lung of the rats with acute lung injury was studied. The results demonstrated that the concentration of endothelin in the lung of the rats in therapy group was lower than that of the injured rats (64.36±5.37 ng/L vs 103.32±4.99 ng/L, P <0.001), and level of serum endothelin was also lower than that of the injured rats (85.35 ng/L vs 113.35 ng/L, P <0.01). PaO 2, serum SOD, lung coefficient, ratio of lung wet weight/dry weight in two groups were also significantly different ( P <0.01) respectively, and the lung pathological injury in the treatment group were less than that of injury group. So it is concluded that astragalus could inhibit the increase of serum and lung endothelin, thereby playing a protective role in the rats with acute lung injury.
文摘To investigate the effects of L-tetrahydropalmatine (L-THP) on ener-gy metabolism, endothelin-1 (ET-1 ) and NO during acute cerebral ischemia-reperfusion of rats, 24 Wistar rats were randomly divided into four groups, with 6rats in each group: sham-operation group, simple ischemia group, ischemia-reperfusion group and treatment group (L-THP group). Cerebral ATP, lactate,ET-1 and NO levels were measured in all groups. Our results showed that treat-ment with L-THP could increase cerebral ATP levels, but decrease cerebral lac-tate, ET-1 and NO concentrations during ischemia-reperfusion in the treatmentgroup. It is concluded that L-THP could improve cerebral energy metabolism and protect the injured brain tissue, the mechanism of which might be related to suppression of overproduction of ET-1 and NO.
基金This project was supported by a grant from national Nat-ural Scienc Foundation of China (No. 39470 6 85 )
文摘The purpose of the present study was to assess the correlation that likely exists among increased portal pressure (P p), portal blood flow quantity (Q p) and ET A and ET B receptor mRNA expression in human cirrhosis. In situ hybridization and reverse transcription polymerase chain reactions (RT PCR) were performed to determine the expression of ET A and ET B receptor mRNA in liver tissues from traumatic subjects ( n =10) and cirrhotic patients ( n =15) in whom hepatic hemodynamic values were measured. The expression of the two transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from traumatic subjects. It has shown that ET A receptor mRNA predominantly located in hepatic stellate cells (HSCs) and vascular smooth muscle cells of intrahepatic arteries and portal veins, ET B receptor mRNA in HSCs, sinusoidal endothelial cells and Kuppfer cells. There was a highly significant direct relationship between ET A and ET B receptor mRNA and P p and Q p in cirrhotic patients. It suggests that liver paracrine endothelin system may be overactivated in human cirrhosis accompanied with increased expression of ET A and ET B receptor mRNA which may play an important role in the pathogenesis and maintenance of splanchnic hyperdynamics.
基金Supported by Indiana University department of surgery and Lilly INGEN research fund provided support for the Research performed in this manuscript
文摘AIM:To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes.METHODS:Wild type,e NOS-/-and i NOS-/-mice receivedpartial portal vein ligation surgery to induce portal hypertension or sham surgery.Development of portal hypertension was determined by measuring the splenic pulp pressure,abdominal aortic flow and portal systemic shunting.To measure splenic pulp pressure,a microtip pressure transducer was inserted into the spleen pulp.Abdominal aortic flow was measured by placing an ultrasonic Doppler flow probe around the abdominal aorta between the diaphragm and celiac artery.Portal systemic shunting was calculated by injection of fluorescent microspheres in to the splenic vein and determining the percentage accumulation of spheres in liver and pulmonary beds.Endothelin-1 hypo-response was evaluated by measuring the change in abdominal aortic flow in response to endothelin-1 intravenous administration.In addition,thoracic aorta endothelin-1contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph.RESULTS:In wild type and i NOS-/-mice splenic pulp pressure increased from 7.5±1.1 mm Hg and 7.2±1 mm Hg to 25.4±3.1 mm Hg and 22±4 mm Hg respectively.In e NOS-/-mice splenic pulp pressure was increased after 1 d(P=NS),after which it decreased and by 7 d was not significantly elevated when compared to 7 d sham operated controls(6.9±0.6 mm Hg and 7.3±0.8 mm Hg respectively,P=0.3).Abdominal aortic flow was increased by 80%and 73%in 7 d portal vein ligated wild type and i NOS when compared to shams,whereas there was no significant difference in 7 d portal vein ligated e NOS-/-mice when compared to shams.Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type,e NOS-/-and i NOS-/-sham mice(50%±8%,73%±9%and 47%±9%respectively).Following portal vein ligation endothelin-1 reduction in blood flow was significantly diminished in each mouse group.Abdominal aortic flow was reduced by 19%±9%,32%±10%and 9%±9%in wild type,e NOS-/-and i NOS-/-mice respectively.CONCLUSION:Aberrant endothelin-1 response in murine portal hypertension is NOS isoform independent.Moreover,portal hypertension in the portal vein ligation model is independent of ET-1 function.
基金supported by the key project of Chinese Ministry of Education(No.109086)
文摘A microwave-assisted solid phase synthesis for endothelin 1 is presented.Reduced endothelin 1 was synthesized efficiently on Wang resin under microwave irradiation using Fmoc/tBu orthogonal protection strategy.The whole peptide was cleaved from the resin and two disulphide bridges were formed under air oxidation at room temperature.The purity and efficiency of synthesizing the peptide is much higher than other methods used before.
