地高辛烷亚基强心作用衍生物的筛选
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摘要
目的：运用离体心脏和动物等多种模型对7个地高辛烷亚基衍生物强心活性进行筛选研究,以期找到具有较好强心作用,同时毒性较低的地高辛衍生物。
方法：使用Langendorff系统正常心脏灌注模型,通过记录心肌张力和左心室内压等心功能指标,对各个衍生物强心活性进行初步评价,获得其半数有效浓度ECso、半数致心律失常浓度AC50等活性参数；建立大鼠离体缺钙心力衰竭模型,采用Langendorff灌流系统评价地高辛衍生物对缺钙诱导的离体大鼠心力衰竭的作用；通过腹腔注射盐酸阿霉素建立了大鼠心力衰竭模型,评价DX-9对在体大鼠心力衰竭的作用。
结果：1.实验测得地高辛EC50=1.969ng/ml, AC50=8.107ng/ml, DX-9EC50=2.585ng/ml AC50=17.343ng/ml.
2.运用低钙心力衰竭模型,发现衍生物DX-9能增加大鼠离体心力衰竭心脏的心肌张力,增加心脏左心室内压(LVSP)。其它6种衍生物对低钙性心力衰竭心脏无影响。
3.DX-9能明显改善阿霉素诱导的心力衰竭大鼠心脏功能,明显增加左心室内压(LVSP)及左室压力最大上升及下降速度(±dp/dtmax),同时降低左心室舒张末压(LVEDP),与地高辛比较,同等剂量的DX-9的作用要弱于地高辛。
结论：通过对7个地高辛烷亚基衍生物的筛选,获得了一个活性较好的地高辛烷亚基衍生物DX-9。在效能相当的情况下,地高辛具有更高的效价强度。我们认为DX-9具有强心作用,是否能成为候选药物还有待于进一步研究。
OBJECTIVE:Using in vitro and in vivo heart failure models, we screened seven digoxin derivatives in order to find a candidate with cardiotonic function and low toxicity.
METHODS:Normal cardiac perfusion Langendorff model was established, myocardial tension, left ventricular pressure and other cardiac function indexs were record, and a preliminary evaluation of the cardiac activity of the various derivatives were carried out to obtain the median effective concentration (EC50), median arrhythmias concentration (AC50) and other activity parameters; calcium deficiency model of heart failure rats in vitro was established, using the Langendorff perfusion system to evaluate the effect of DX-9on the calcium deficiency induced isolated heart failure in rat; Established a rat model of heart failure by intraperitoneal injection of doxorubicin hydrochloride, to evaluate the effect of DX-9on the doxorubicin-induced heart failure in rat.
RESULTS:
1. We found the EC50and AC50of digoxin and DX-9respectively, as follow: digoxin EC50=1.969ng/ml, AC50=8.107ng/ml, DX-9EC50=2.585ng/ml, AC50=17.343ng/ml.
2. DX-9increased myocardial tension and pressure within the left ventricle in a dose-dependent manner on the calcium deficiency induced isolated heart failure in rat.
3. The DX-9significantly improved cardiac function of doxorubicin-induced rat heart failure, significant increased in the maximum rise and fall speed of the left ventricular pressure (LVSP) and left ventricular pressure (±dp/dt max), while weakened Left Ventricular End-Diastolic Pressure (LVEDP).Compared with digoxin, the effect of the same dose of DX-9was weaker than digoxin.
CONCLUSION:We found a digoxin derivative with cardiotonic function from7digoxin derivatives. On the same performance, digoxin has a higher potency. We think the DX-9has cardiotonic activity, if it can become a drug candidate remains to be studied further.
方法：使用Langendorff系统正常心脏灌注模型,通过记录心肌张力和左心室内压等心功能指标,对各个衍生物强心活性进行初步评价,获得其半数有效浓度ECso、半数致心律失常浓度AC50等活性参数；建立大鼠离体缺钙心力衰竭模型,采用Langendorff灌流系统评价地高辛衍生物对缺钙诱导的离体大鼠心力衰竭的作用；通过腹腔注射盐酸阿霉素建立了大鼠心力衰竭模型,评价DX-9对在体大鼠心力衰竭的作用。
结果：1.实验测得地高辛EC50=1.969ng/ml, AC50=8.107ng/ml, DX-9EC50=2.585ng/ml AC50=17.343ng/ml.
2.运用低钙心力衰竭模型,发现衍生物DX-9能增加大鼠离体心力衰竭心脏的心肌张力,增加心脏左心室内压(LVSP)。其它6种衍生物对低钙性心力衰竭心脏无影响。
3.DX-9能明显改善阿霉素诱导的心力衰竭大鼠心脏功能,明显增加左心室内压(LVSP)及左室压力最大上升及下降速度(±dp/dtmax),同时降低左心室舒张末压(LVEDP),与地高辛比较,同等剂量的DX-9的作用要弱于地高辛。
结论：通过对7个地高辛烷亚基衍生物的筛选,获得了一个活性较好的地高辛烷亚基衍生物DX-9。在效能相当的情况下,地高辛具有更高的效价强度。我们认为DX-9具有强心作用,是否能成为候选药物还有待于进一步研究。
OBJECTIVE:Using in vitro and in vivo heart failure models, we screened seven digoxin derivatives in order to find a candidate with cardiotonic function and low toxicity.
METHODS:Normal cardiac perfusion Langendorff model was established, myocardial tension, left ventricular pressure and other cardiac function indexs were record, and a preliminary evaluation of the cardiac activity of the various derivatives were carried out to obtain the median effective concentration (EC50), median arrhythmias concentration (AC50) and other activity parameters; calcium deficiency model of heart failure rats in vitro was established, using the Langendorff perfusion system to evaluate the effect of DX-9on the calcium deficiency induced isolated heart failure in rat; Established a rat model of heart failure by intraperitoneal injection of doxorubicin hydrochloride, to evaluate the effect of DX-9on the doxorubicin-induced heart failure in rat.
RESULTS:
1. We found the EC50and AC50of digoxin and DX-9respectively, as follow: digoxin EC50=1.969ng/ml, AC50=8.107ng/ml, DX-9EC50=2.585ng/ml, AC50=17.343ng/ml.
2. DX-9increased myocardial tension and pressure within the left ventricle in a dose-dependent manner on the calcium deficiency induced isolated heart failure in rat.
3. The DX-9significantly improved cardiac function of doxorubicin-induced rat heart failure, significant increased in the maximum rise and fall speed of the left ventricular pressure (LVSP) and left ventricular pressure (±dp/dt max), while weakened Left Ventricular End-Diastolic Pressure (LVEDP).Compared with digoxin, the effect of the same dose of DX-9was weaker than digoxin.
CONCLUSION:We found a digoxin derivative with cardiotonic function from7digoxin derivatives. On the same performance, digoxin has a higher potency. We think the DX-9has cardiotonic activity, if it can become a drug candidate remains to be studied further.
引文
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