Left-ventricular dysfunction, heart vagus influences and angiotensin II effects after doxorubicin perfusion in isolated rat hearts

Journal of Clinical and Basic Cardiology 1999; 2 (2): 259-266

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Keywords: Angiotensin II,  doxorubicin,  Elektrokardiographie,  Myokardfunktion,  Vagusstimulation,  Angiotensin II,  doxorubicin,  ECG,  myocardial function,  vagus stimulation

Chronic treatment with doxorubicin (DXR) or other anthracyclines causes impairments in myocardial function and, eventually, results in dilatative cardiomyopathy (DCM). It is also associated with changes in the action of the renin-angiotensin II (AII) system and AII receptor density. Aim of the present study was to investigate effects of DXR perfusion (up to 60 min) of isolated, vagally innervated rat hearts on vagus effects regarding cardiac activity and possible changes by DXR in the modulation of vagus effects by angiotensin II (AII), for comparison with known chronic anthracycline effects. Electrical (surface ECG) and mechanical (left-ventricular pressure, LVP) cardiac activity were recorded. Vagus stimulation (10 Hz, 10 V) caused prolonged ECG intervals, reduced heart rate (HR) and negative inotropic effects (reduced left-ventricular systolic pressure PS, decelerated contraction). Perfusion with DXR-containing Tyrode (10-40 µmol/L DXR) caused dose-dependent and progressive functional impairments, similar to those known from long-term anthracycline treatment in humans: prolonged ECG intervals, decreased HR, reduced PS and a prolonged contraction period. The effects of heart vagus stimulation on ECG and LVP were reduced during DXR perfusion. However, DXR perfusion did not affect the positive chronotropic and inotropic effects of AII (1 µmol/L, applied subsequently to DXR) as well as the modulatory function of AII on cardiac vagus actions: AII blocking effects were comparable to control. These results are at some variance with clinical findings in long-term anthracycline treatment. It is concluded that short-time DXR administration was not enough for establishing changes in the AII system observed during long-term treatment. J Clin Basic Cardiol 1999; 2: 259-66.