The age-related response of the myocardium to 30 min of 37-degrees-C global ischemia and 120 min of 37-degrees-C reperfusion, measured by phosphorus-31 magnetic resonance spectroscopy and the recovery of isovolumic function, was evaluated by using perfused neonatal (3-8 days old, n = 10), immature (24-30 days old, n = 10), and adult (2-4 mo old, n = 5) rabbit hearts. Basal intracellular pH (pH(i)) was highest in neonatal hearts and decreased with age. The basal phosphocreatine (PCr)-to-ATP ratio differed in each group, increasing with age. Rapid depletion of PCr occurred in all groups during ischemia; ATP retention was greater in adults than in neonates. Reperfusion resulted in no measurable recovery of ATP in any group. Postischemic pH(i) stabilized above preischemic values in neonatal and immature hearts and below preischemic values in adult hearts. Recovery of PCr and cytosolic P(i) (P(i)cy) content, heart rate, and coronary flow during reperfusion was greater in neonatal and immature than in adult hearts. During the final 20 min of ischemia, pH(i) was lower in immature than in neonatal or adult hearts. Postischemic recovery of left ventricular maximum rate of pressure rise (+dP/dt(max)) was depressed in immature compared with neonatal and adult hearts. These results demonstrate increased tolerance of the neonatal heart and increased susceptibility of the immature heart to unprotected normothermic ischemic injury relative to the adult heart and suggest that maturational changes in myocardial pH(i) regulation may be responsible for the observed age-related response.