The role of catecholamines in ischemic preconditioning is unclear. Accordingly, the effects of tyramine-induced norepinephrine release and alpha1-receptor blockade were examined. Ischemic preconditioning with a 5-minute coronary occlusion 10 minutes before a 30 -minute ischemic interval resulted in only 7.7+/-3.1% infarction of the risk area, significantly less than that in control rabbits with isolated 30-minute coronary occlusions (34.4+/-3.2%, P<.01). Intravenous infusion of tyramine 10 minutes before 30 minutes of ischemia also protected the heart from infarction to an extent similar to that seen with ischemic preconditioning (6.9+/-2.4% infarction). This protection observed with tyramine infusion was eliminated by alpha1-receptor blockade with BE 2254 (36.8+/-2.6% infarction) but was unaffected by beta-blockade with propranolol (10.5+/-2.4% infarction). Furthermore, the protection was unaffected when the tyramine-induced hypertension was attenuated by allowing blood to flow into a volume reservoir (3.9+/-0.8% infarction, P<.01 vs control value). The nonselective adenosine-receptor blocker PD 115,199 also eliminated tyramine-induced protection (40.2+/-5.6% infarction), indicating that adenosine is involved in adrenergic-mediated protection. BE 2254 could not block ischemic preconditioning (3.9+/-1.1% infarction, P<.01 vs control value). Therefore, catecholamine release before prolonged ischemia can protect the heart from infarction via the alpha1-receptor, but adenosine receptor stimulation is also involved. Alpha-Adrenergic stimulation does not appear to be critical to the protection observed after ischemic preconditioning.