Phenylphthalazines化合物PU_(1424)的利尿作用分析
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摘要
目的检测Phenylphthalazines化合物PU_(1424)对大鼠的利尿作用,以及利尿后对电解质平衡、糖脂代谢及肝脏、肾脏功能的影响。方法以♂SD大鼠为研究对象,随机分为溶剂对照组、PU_(1424)组和氢氯噻嗪(hydrochlorothiazide,HCTZ)组,连续给药后每6 h收集尿液,末次给药后取血。采用冰点渗透仪检测大鼠尿液的渗透压;尿素检测试剂盒检测尿素水平;全自动生化仪分析尿液及血浆的离子水平、血糖、血脂和肝肾功能指标。结果 PU_(1424)和HCTZ分别增加大鼠尿量为对照组的1.52倍和1.78倍,降低尿渗透压为对照组的61.5%和50.4%,降低尿尿素浓度为对照组的57.1%和56.8%,饮水量增加为对照组的1.42倍和1.56倍。PU_(1424)和HCTZ的利尿作用降低了尿液中的电解质水平,但对血浆电解质平衡无明显影响。PU_(1424)组大鼠的血糖、血脂水平与溶剂对照组相比无明显差异,而HCTZ升高了血糖和总胆固醇。PU_(1424)和HCTZ对大鼠血清中尿素、肌酐水平无明显影响,PU_(1424)对大鼠血清中谷丙转氨酶/谷草转氨酶(谷丙/谷草)、碱性磷酸酶和总蛋白、白蛋白水平无明显影响,HCTZ可升高血清谷丙/谷草比值。结论新型利尿药候选化合物PU_(1424)利尿作用明显,且不影响机体的电解质平衡、血糖血脂水平和肝脏、肾脏功能。
Aim To study on the diuretic effect of a phenylphthalazines compound PU_(1424) and its influence on electrolyte balance,glucose and lipid metabolism,hepatic and renal functions.Methods Male Sprague Dawley rats were randomly divided into solvent control group,PU_(1424) treated group and HCTZ treated group.Urine was collected per 6 h and blood samples were collected at the end of drug administration.Urinary osmolality was measured by Freezing Point Osmometer;urea concentration was measured by Urea Detection Kit;ion level,blood glucose level,blood lipid level,hepatic and renal function were analyzed by Automatic Biochemical Analyzer.Results Compared to the solvent control group,and urine output of rats treated with PU_(1424) and HCTZ was increased as 1.52 times and1.78 times and water intake increased as 1.42 times and 1.56 times respectively.Urine osmolalities were decreased as 61.5% and 50.4% of the control group,and urine urea concentration was decreased as 57.1%and 56.8% of the control group.Urinary electrolytes were decreased by administration of PU_(1424) and HCTZ compared to the intact plasma electrolytes.The blood glucose levels and blood lipid levels of rats treated with PU_(1424) had no changes,while the blood glucose and total cholesterol were increased by administration of HCTZ.The urea nitrogen,creatinine,alkaline phosphatase and total protein were intact by administration of PU_(1424) and HCTZ except the alanine/straw ration increased by HCTZ.Conclusion New diuretic candidate compound PU_(1424) displays significant diuretic effect with electrolyte balance,blood glucose level,blood lipid level,hepatic and renal function intact.
Aim To study on the diuretic effect of a phenylphthalazines compound PU_(1424) and its influence on electrolyte balance,glucose and lipid metabolism,hepatic and renal functions.Methods Male Sprague Dawley rats were randomly divided into solvent control group,PU_(1424) treated group and HCTZ treated group.Urine was collected per 6 h and blood samples were collected at the end of drug administration.Urinary osmolality was measured by Freezing Point Osmometer;urea concentration was measured by Urea Detection Kit;ion level,blood glucose level,blood lipid level,hepatic and renal function were analyzed by Automatic Biochemical Analyzer.Results Compared to the solvent control group,and urine output of rats treated with PU_(1424) and HCTZ was increased as 1.52 times and1.78 times and water intake increased as 1.42 times and 1.56 times respectively.Urine osmolalities were decreased as 61.5% and 50.4% of the control group,and urine urea concentration was decreased as 57.1%and 56.8% of the control group.Urinary electrolytes were decreased by administration of PU_(1424) and HCTZ compared to the intact plasma electrolytes.The blood glucose levels and blood lipid levels of rats treated with PU_(1424) had no changes,while the blood glucose and total cholesterol were increased by administration of HCTZ.The urea nitrogen,creatinine,alkaline phosphatase and total protein were intact by administration of PU_(1424) and HCTZ except the alanine/straw ration increased by HCTZ.Conclusion New diuretic candidate compound PU_(1424) displays significant diuretic effect with electrolyte balance,blood glucose level,blood lipid level,hepatic and renal function intact.
引文
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[2]Faris R,Flather M,Purcell H,et al.Current evidence supporting the role of diuretics in heart failure:a meta analysis of randomised controlled trials[J].Int J Cardiol,2002,82(2):149-58.
[3]Barzilay J I,Davis B R,Pressel S L,et al.Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension the ALLHAT diabetes extension study[J].Circ Cardiovasc Qual Outcomes,2012,5(2):148-9.
[4]Zillich A J,Garg J,Basu S,et al.Thiazide diuretics,potassium,and the development of diabetes:a quantitative review[J].Hypertension,2006,48(2):219-24.
[5]Yao C,Anderson M O,Zhang J,et al.Triazolothienopyrimidine inhibitors of urea transporter UT-B reduce urine concentration[J].J Am Soc Nephrol,2012,23(7):1210-20.
[6]Li F,Lei T,Zhu J,et al.Novel small-molecule thienoquinolin urea transporter inhibitor acts a potential diuretic[J].Kidney Int,2013,83(6):1076-86.
[7]Ren H,Wang Y,Xing Y,et al.Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters[J].Am J Physiol Renal Physiol,2014,307(12):F1363-72.
[8]Ran J H,Li M,Yang B X,et al.Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model[J].Acta Pharmacol Sin,2016,37(7):973-83.
[9]Sands J M.Renal urea transporters,curr opin nephrol hypertens[J].2004,13(5):525-32.
[10]Yang B,Bankir L.Urea and concentrating ability:new insights from studies in mice[J].Am J Physiol Renal Physiol,2005,288(5):F881-96.
[11]Klein J D,Blount M A,Sands J M.Urea Transport in the kidney[J].Compr Physiol,2011,1(2):699-729.
[12]Bankir L,Chen K,Yang B.Lack of UT-B in vase recta and red blood cells prevents urea-induced improvement of urinary concentrating ability[J].Am J Physiol Renal Physiol,2004,286(1):F144-51.
[13]Fenton R A,Flynn A,Shodeinde A.Renal phenotype of UT-A urea transporter knockout mice[J].J Am Soc Nephrol,2005,16(6):1583-92.
[14]Esteva-Font C,Anderson M O,Verkman A S.Urea transporter proteins as targets for small-molecule diuretics[J].Nat Rev Nephrol,2015,11(2):113-23.
[15]Marazzi G,Volterrani M,Caminiti G,et al.Effectiveness of nebivolol and hydrochlorothiazide association on blood pressure,glucose,and lipid metabolism in hypertensive patients[J].Adv Ther,2010,27(9):655-64.