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
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
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
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.
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.
