The authors have shown that stimulation of cardiac alpha 1-adrenoceptors confers immediate cardioprotection in the isolated rat heart against post-ischemic dysfunction, and have recently demonstrated that in vivo treatment of rats with norepinephrine (NE) induces cardiac heat shock protein 72 and myocardial adaptation to ischemia 24 h after treatment. To characterize the delayed myocardial adaptive response induced by NE further, the present study examined its time course and effects of adrenoceptor antagonism and protein synthesis inhibition on this adaptive response during optimal myocardial protection. Rats were treated with NE (3.1 mumol/kg, i.p.) or normal saline (0.4 ml, i.p.), and hearts isolated at 2, 4, 24, 72 and 168 h after injection. Isolated hearts were subjected to 25 min of normothermic global ischemia and 40 min of reperfusion by the Langendorff technique, and left ventricular developed pressure (LVDP) was assessed. There was no difference in baseline LVDP among groups. Post-ischemic LVDP recovered to 44.7 +/- 2.1 mmHg in pooled saline control. LVDP was significantly improved in hearts isolated at 4, 24 and 72 h after injection of NE (66.3 +/- 3.8, 68.6 +/- 2.7 and 72.6 +/- 8.3 mmHg, respectively, P < 0.05 v control) but not in hearts isolated at 2 or 168 h. Effects of antecedent adrenoceptor antagonism and protein synthesis inhibition were examined in hearts isolated at 72 h after NE treatment. Prazosin pretreatment (2.4 mumol/kg, i.p.) abolished the delayed myocardial adaptive response induced by NE at 72 h (post-ischemic LVDP 48.3 +/- 6.1 mmHg, P > 0.05 v control) while propranolol pretreatment (3.4 mumol/kg, i.p.) had no effect (post-ischemic LVDP 67.3 +/- 3.7 mmHg, P < 0.05 v control). Cycloheximide pretreatment (3.6 mumol/kg, i.p.) also abolished the beneficial effect of NE at 72 h (post-ischemic LVDP 50.2 +/- 6.0 mmHg, P > 0.05 v control). In conclusion, administration of NE to rats can induce delayed and sustained cardioprotection against post-ischemic myocardial dysfunction. NE-induced myocardial adaptation to ischemia at 72 h is mediated by alpha 1-adrenoceptors and appears to require protein synthesis.