Acute, high intensity stress induces necrotic lesions in heart. We found that restraint and cold (4°C) exposure (RCE) raises plasma lactate dehydrogenase, creatine kinase and transaminase activity in a time-dependent manner, with a peak value 7 h after stimulus cessation. At 24 h, signs of necrotic lesions were observed in paraffin sections stained with hematoxylin-eosin: focal accumulation of mononuclear cells in subendocardial areas of the left ventricle wall and focal hemorrhage in papillary muscles. In contrast, inter-male fighting (IF) did not increase plasma creatine kinase activity, although lactate dehydrogenase and transaminases activities did increase. In IF, no histological evidence of heart injury was observed. Since IF, but not RCE, increased plasma epidermal growth factor (EGF) concentration by nearly 1000-fold, we hypothesized that EGF receptor (ErbB1) activation may protect the heart against stress-induced injury. To examine this hypothesis, we injected the ErbB1 tyr kinase inhibitor tyrphostin AG1478 (25 mg/Kg, i.p.) immediately before mice were exposed to IF. Three hours afterwards, plasma activities of lactate dehydrogenase-1 and creatine kinase increased. Control mice (injected with vehicle alone) had plasma enzyme activities as low as non-fighting mice. In the last experiment, we injected EGF (0.25 mg/Kg, i.p.) 20 min before exposing mice to RCE. After 7 h, plasma lactate dehydrogenase-1 and creatine kinase activities were significantly lower in these animals than in mice injected with vehicle. The effect required ErbB1 activation because simultaneous administration of AG1478 completely abolished the effect of exogenous EGF. We conclude that activated ErbB1, by either endogenous or exogenous ligands, may protect the heart against stress-induced injury.