Recent data suggests that -adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function versus cardiac remodeling. To dissect the roles of 1 vs. 2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to 1, 2, and 1/2 knockout (^-/-) and wildtype mice. Expression and activation of MAPKs were measured. Wildtype and 1^-/- mice showed no acute cardiovascular effects whereas 2^-/- mice all died within 30 min. The additional deletion of the 1-receptor (1/2^-/-) totally rescued this toxicity. 2^-/- mice developed decreased contractile function, hypotension, QTc prolongation and ST segment changes, and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB203580 rescued beta2^-/- mice from this acute toxicity. The enhanced toxicity in 2^-/- mice was also recapitulated in wildtype mice with the 2-selective antagonist ICI 118,551, although the rescue effect of the 1 deletion was not recapitulated using the 1-selective antagonist metoprolol or the non-selective -antagonist propranolol. These data suggest that 2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas 1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate -agonist as well as doxorubicin cardiotoxicity, appear to play a role in mediating the differential effects of these -AR subtypes in vivo.