INVITRO EVALUATION OF ACUTE EFFECTS OF MITOXANTRONE (NOVANTRONE(R)) IN RAT AND GUINEA-PIG ATRIA

Since guinea pig and rat atria have been used as models to study acute anthracycline-induced cardiotoxicity, experiments were carried out in these preparations to evaluate possible acute cardiac effects mediate d by mitoxantrone (MTX). After a latency period of approximately 90 mi n, MTX (10(-5)- 10(-4) M) promoted a concentration-related and time-de pendent decrease of spontaneous rate in guinea pig atria. A similar bu t less intense effect after a longer latency interval was observed in rat atria. In this preparation, MTX (10(-5)- 10(-4) M) incubated up to 150 min., induced a gradual competitive beta-adrenergic blocking effe ct on the positive chronotropic action of isoproterenol. This was char acterized by a progressive decline of pD2 values without altering E(ma x). A similar and stronger effect was found in isolated guinea pig atr ia incubated under same conditions with MTX, except that 10(-4) M expo sed for 150 min. was able to depress the E(max) to isoproterenol by 21 .2%. In addition, MTX (10(-4) M) in this model promoted a non-competit ive antagonistic effect on the chonotropic action of histamine. These data are compatible with the idea that MTX could induce cardiac acute effects qualitatively similar to but of lower potency than those produ ced by doxorubicin in these two models. In addition, guinea pig atria seemed to display higher sensitivity to MTX compared to rat atrial pre parations.