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
The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12...The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12）, b = 14.259（2）, c = 19.712（3） A, V= 1933.5（6） A3, Z = 4, Dc = 1.300 g/cm3, f（000） = 800, μ= 0.090 mm-1, the final R = 0.0324 and wR = 0.0775 for 2410 observed reflections （I 〉 2σ（I））. The structure, especially the absolute configuration, of the title compound ambrisentan, an important endothelin receptor antagonist, was confirmed by single- crystal X-ray diffraction. The three aromatic rings in the lattice are basically orthogonal to one another. There is an intermolecular hydrogen bond in the crystal, which helps to further stabilize the crystal. One of the two non-classical intramolecular hydrogen bonds can help to stabilize the molecular conformation in the lattice.展开更多
Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6...Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .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
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.
基金Supported by the Key Project of National Innovative Drug of China(2009ZX09301-008-P-05)the Science Foundation of Tianjin (12JCYBJC18800-2012)
文摘The title compound was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. The crystal is of orthorhombic system （C22H22N2O4, Mr = 378.42）, space group P2121 with a = 6.8786（12）, b = 14.259（2）, c = 19.712（3） A, V= 1933.5（6） A3, Z = 4, Dc = 1.300 g/cm3, f（000） = 800, μ= 0.090 mm-1, the final R = 0.0324 and wR = 0.0775 for 2410 observed reflections （I 〉 2σ（I））. The structure, especially the absolute configuration, of the title compound ambrisentan, an important endothelin receptor antagonist, was confirmed by single- crystal X-ray diffraction. The three aromatic rings in the lattice are basically orthogonal to one another. There is an intermolecular hydrogen bond in the crystal, which helps to further stabilize the crystal. One of the two non-classical intramolecular hydrogen bonds can help to stabilize the molecular conformation in the lattice.
文摘Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .
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.
