Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple...Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：展开更多
Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ...Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.展开更多
Renal ischemia reperfusion injury increases renal generation of angiotensin II （Ang Ⅱ） which could wors- en renal vasocontraction. Thus, we investigated the hypothesis that renal ischemia reperfusion injury alters ...Renal ischemia reperfusion injury increases renal generation of angiotensin II （Ang Ⅱ） which could wors- en renal vasocontraction. Thus, we investigated the hypothesis that renal ischemia reperfusion injury alters renal af- ferent arteriolar responses to Ang II via production of hydrogen peroxide （ H202 ）, or superoxide （ O2 ） or via al- tered angiotensin type 1 receptor （AT1R） expression. Afferent arterioles of mouse kidneys 24h after renal ischemia repeffusion or sham procedures were isolated and perfused. Responses to Ang II or norepinephrine （NE） were as- sessed by measurement of arteriolar luminal diameter. The mRNA expressions of AT1 receptor （ AT1 R） and AT2 re- ceptor （ATzR） were evaluated by quantificational real-time polymerase chain reaction. Compared to sham group, afferent arterioles from mouse kidneys after renal ischemia reperfusion had impaired contractions to Ang II （ -4.63 ± 3.06） % versus （ - 29.95 ± 1.31 ） % at 10 -9 tool · ^-1, p 〈 0.05 , （ - 27.07 ± 1 50） % versus （ - 41 74 ± 0.60） % at 10^-7 tool · L^-1, P 〈 0.05 ） that were normalized by incubation with PEG-catalase , but unaffected by PEG-SOD. However, the NE responses of afferent arterioles after renal ischemia reperfusion were unchanged. Com- pared to the sham group, renal ischemia reperfusion significantly increased the renal cortical H202 （0. 123 ± -1 0. 006） versus （0. 087 ± 0. 003） mmol·mg protein, P 〈 0.01 ）, reduced catalase activity [ （ 14.81 ± 3.22） ver- sus （28.49 ± 1.62） units · mg^-1 protein, P 〈 0.01 ] and downregulated mRNA for AT1R （0.27 ± 0.02 versus 0.95 ± 0.02, P 〈 0.01 ）. We conclude that afferent arteriolar responses to Ang II are impaired selectively in mice after renal ischemia reperfusion by accumulation of H202 and reduced expression of AT1R.展开更多
OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METH...OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.展开更多
Objective Vascular endothelial cells senescence is one of major risk factors for atherosclerotic diseases,which can be induced by endogenous peptides,such as angiotensin Ⅱ(Ang Ⅱ).However,the effect of chronic Ang Ⅱ...Objective Vascular endothelial cells senescence is one of major risk factors for atherosclerotic diseases,which can be induced by endogenous peptides,such as angiotensin Ⅱ(Ang Ⅱ).However,the effect of chronic Ang Ⅱ stimulation on endothelial senescence remains unknown.Therefore,this study aims to investigate the changes in morphology and function of human umbilical vein endothelial cells(HUVECs)in response to the chronic stimulation of Ang Ⅱ.展开更多
Objective To investigate the combined effects of hypertension and angiotensinⅡon the risk of coronary heart disease(CHD)on the basis of a 10-year prospective study in an Inner Mongolian population of China.Methods Ba...Objective To investigate the combined effects of hypertension and angiotensinⅡon the risk of coronary heart disease(CHD)on the basis of a 10-year prospective study in an Inner Mongolian population of China.Methods Based on a cross-sectional survey,a prospective cohort study was conducted from June 2003 to July 2012 among 2,530 Mongolian people.展开更多
基金Project(20876180)supported by the National Natural Science Foundation of China
文摘Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：
文摘Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.
文摘Renal ischemia reperfusion injury increases renal generation of angiotensin II （Ang Ⅱ） which could wors- en renal vasocontraction. Thus, we investigated the hypothesis that renal ischemia reperfusion injury alters renal af- ferent arteriolar responses to Ang II via production of hydrogen peroxide （ H202 ）, or superoxide （ O2 ） or via al- tered angiotensin type 1 receptor （AT1R） expression. Afferent arterioles of mouse kidneys 24h after renal ischemia repeffusion or sham procedures were isolated and perfused. Responses to Ang II or norepinephrine （NE） were as- sessed by measurement of arteriolar luminal diameter. The mRNA expressions of AT1 receptor （ AT1 R） and AT2 re- ceptor （ATzR） were evaluated by quantificational real-time polymerase chain reaction. Compared to sham group, afferent arterioles from mouse kidneys after renal ischemia reperfusion had impaired contractions to Ang II （ -4.63 ± 3.06） % versus （ - 29.95 ± 1.31 ） % at 10 -9 tool · ^-1, p 〈 0.05 , （ - 27.07 ± 1 50） % versus （ - 41 74 ± 0.60） % at 10^-7 tool · L^-1, P 〈 0.05 ） that were normalized by incubation with PEG-catalase , but unaffected by PEG-SOD. However, the NE responses of afferent arterioles after renal ischemia reperfusion were unchanged. Com- pared to the sham group, renal ischemia reperfusion significantly increased the renal cortical H202 （0. 123 ± -1 0. 006） versus （0. 087 ± 0. 003） mmol·mg protein, P 〈 0.01 ）, reduced catalase activity [ （ 14.81 ± 3.22） ver- sus （28.49 ± 1.62） units · mg^-1 protein, P 〈 0.01 ] and downregulated mRNA for AT1R （0.27 ± 0.02 versus 0.95 ± 0.02, P 〈 0.01 ）. We conclude that afferent arteriolar responses to Ang II are impaired selectively in mice after renal ischemia reperfusion by accumulation of H202 and reduced expression of AT1R.
基金The project supported by National Natural Science Foundation of China(81102444)the Major Scientific and Technological Special Project for"Significant New Drugs Creation"(2009ZX09302-003,2013ZX09508104)the Central Public Scientific Research Institution Fundamental Project(2014CX05)
文摘OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.
文摘Objective Vascular endothelial cells senescence is one of major risk factors for atherosclerotic diseases,which can be induced by endogenous peptides,such as angiotensin Ⅱ(Ang Ⅱ).However,the effect of chronic Ang Ⅱ stimulation on endothelial senescence remains unknown.Therefore,this study aims to investigate the changes in morphology and function of human umbilical vein endothelial cells(HUVECs)in response to the chronic stimulation of Ang Ⅱ.
文摘Objective To investigate the combined effects of hypertension and angiotensinⅡon the risk of coronary heart disease(CHD)on the basis of a 10-year prospective study in an Inner Mongolian population of China.Methods Based on a cross-sectional survey,a prospective cohort study was conducted from June 2003 to July 2012 among 2,530 Mongolian people.
