The roles of NO synthase and ATP-dependent K+ channels (KATP channels) in the development of the infarct-limiting effect of early hypoxic preconditioning (HP) in rats were studied and the potential for pharmacological simulation of this phenomenon was demonstrated. HP was modeled by alternation of six 10-min sessions of normobaric hypoxia (8% O2) and six 10-min periods of reoxygenation with atmospheric oxygen (21% O2). The total duration of the adaptive action was 120 min. These results indicate that NO synthase and KATP channels play the role of mediators in the signal mechanism of HP. NO donors and KATP channel activators allow the protective effect of hypoxic preconditioning to be reproduced by administration 1 h before ischemia/reperfusion but not when given 2 h 30 min before coronary occlusion.