Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovacular disease remain to be elucidated. An established animal model of stress in humans is the pre-natally stressed rat (PS). We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (Control)were further subjected to restraint stress (R) at 6 and 7 weeks of age. Echocardiography revealed a significant decrease in fractional shortening in PS +R vs Controls +R (% FS) (45.8±3.9 vs 61.9±2.4; PS +R vs Controls +R; p<0.01; n=12). Isolated adult rat ventricular myocytes (ARVM) from PS +R also revealed diminished % FS (6.7±0.8 vs 12.7±1.1; PS +R vs Controls + R; p<0.01; n=24) and blunted inotropic responses to isoproterenol (p<0.01;n=24) determined by automated border detection. The p38 MAP kinase inhibitor, SB 203580, blocked p38 MAP kinase phosphorylation and significantly reversed the depression in % FS and blunted adrenergic signaling seen in ARVM from PS +R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.