A Screen Of Digoxin Derivative With Cardiotonic Function

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.