Clinical reports suggest that emotional stress alone is sufficient to cause profound, but completely reversible myocardial dysfunction in patients. We previously reported that a combination of pre-natal and post-natal behavioral stresses results in myocardial dysfunction in a rodent model (Stress). Stress demonstrates both systolic (+dp/dt) and diastolic (+dp/dt) dysfunction by catheter-based hemodynamics, as well as, significantly attenuated hemodynamic and inotropic responses to the beta adrenergic agonist, isoproterenol in vivo and in vitro compared with matched controls (p<.05, for all). The p38 MAP kinase inhibitor, SB203580 , both prevented and reversed the baseline reduction in +dp/dt and +dp/dt, as well as the blunted isoproterenol response in vivo and cardiac myocyte dysfunction in vitro (p<.05, for each). These physiologic defects are associated with decreased myocardial ATP and GSH/GSSG levels compared with matched controls (p<.05). We conclude that p38 MAP kinase activation in cardiac myocytes in response to enhanced oxidative stress may be at least partially responsible for reversible myocardial dysfunction in this animal model of behavioral stress.