The role of endothelin-1 in the doxorubicin cardiotoxicity

Background: The cardiotoxicity of doxorubicin (Dx), an antineoplastic drug, is imposed by the development of cardiomyopathy and heart failure. The expression of endothelin-1 (ET-1) in myocardium under the action of Dx, directly correlates with the degree of cardiac dysfunction, mediated by endothelin A (ETA) receptor.

Material and methods: For prospective randomized study 2 groups of white rats (experimental group n=9, control group n=9) were used. During 2 weeks in the control group was administrated Dx (i/p, 4mg/kg in one dose, twice/week), cumulative dose – 16 mg/kg. The ET-1 effects were estimated at its peak action in concentration 10-7 M (mol), reproduced after 30 sec of endothelin stimulation.

Results: The functional parameters of isolated heart perfused in physiologic regime and in condition of volume and resistance overload under the ET-1 action in the group with Dx compared with the control one, were reduced considerably, namely: cardiac output (CO); left ventricle systolic pressure (LVSP); left ventricle end-diastolic pressure (LVEDP).

Conclusions: Under the ET-1 action on the isolated heart perfused in physiologic regime in the group with Dx – the LVSP and CO were reduced determining negative inotropic effect. At the volume overload test, under the ET-1 action, the diastolic impairment was more evident in the group with Dx, due to increased LVEDP. At the resistance overload test under the ET-1 action, the CO was reduced indicating the depreciation of myocardial contraction capacity.