An intracellular mechanism that senses decreases in tissue oxygen level and stimulates hypoxia-related gene expression has been reported in various cell types including the cardiac cell. The mechanism can also be activated by Co(2+) in normoxia. Thus we investigated the effects of prior chronic oral CoCl(2) on mechanical functions of isolated, perfused rat hearts in hypoxia-reoxygenation. In normoxic rats, 43 days of Co(2+) administration increased hematocrit from 45 +/- 0.3% (control, n = 18) to 51 +/- 0.6% (n = 19). In hypoxia and reoxygenation, Co(2+)-pretreated hearts exhibited a significantly higher rate-pressure product (267 and 163%, respectively) and coronary flow (127 and 118%, respectively) and lower end-diastolic pressure (72 and 60%, respectively) compared with the control hearts. Although the oral Co(2+) administration significantly raised myocardial Co(2+) concentration, it did not affect mitochondrial respiration, tissue glycogen concentration, or myocardial tissue histology. The levels of vascular endothelial growth factor, aldolase-A, and glucose transporter-1 mRNA were significantly elevated in the Co(2+)-treated myocardium. We conclude that cardiac contractile functions would gain hypoxic tolerance when the endogenous cellular oxygen-sensing mechanism is activated.