Acute effects of doxorubicin on chronotropic and inotropic mechanisms in guinea pig atria.

This study was designed to test the possible acute effects of doxorubicin (DOX) on isolated guinea pig atria incubated in Locke's solution. Different concentrations of DOX (10(-6) to 10(-4) M) were added to the medium 30 minutes before the concentration-response curves to noradrenaline and histamine were carried out. DOX (10(-4) M) significantly reduced spontaneous atrial rate. Atropine (10(-6) g/ml) was unable to modify this cardiodepressant effect. DOX (10(-4) M) produced a competitive beta blocking effect, shifting to the right the concentration-response curve to noradrenaline without altering the maximal chronotropic response. On the other hand, this anthracycline (10(-4) M) not only antagonized chronotropic responses to histamine, but significantly reduced the maximal effect mediated by this amine. Isolated left guinea pig atria electrically paced were used to determine the effects of DOX on positive inotropic activity promoted by noradrenaline and histamine. Similarly to what was observed in chronotropic experiments, DOX (10(-4) M) produced a competitive beta blocking action and a noncompetitive inhibition of the positive inotropic action developed by histamine. Lower concentrations of DOX failed to modify the chronotropic responses to both amines. However, after 60 minutes of incubation with DOX, 10(-5) M of this drug produced a shift to the right of the concentration-response curves to noradrenaline and histamine and depressed the maximal chronotropic response to these amines. These effects were not observed with 3 X 10(-6) M DOX. These results are compatible with the idea that a nonspecific interaction of DOX with cardiac beta and histaminergic receptors could be involved in the acute cardiotoxic mechanism produced by this anthracycline.