Metabolic regulatory mechanisms are designed to maintain stable myocardial function during extremes in physiological insult; they can now be studied in vivo and may provide insight into mechanisms of altered myocardial functional decompensation during disease processes. To determine mechanisms of myocardial stability during hypoxia and acute pressure loading, creatine kinase (CK) kinetics (forward rate constant, K<sub>f</sub>, and flux of phosphocreatine, PCr, to adenosine triphosphate, ATP), and nicotinamide adenine dinucleotide (NADH) redox state were determined with <sup>31</sup>P nuclear magnetic resonance (NMR) and NADH fluorometry, respectively, and correlated with heart work (heart rate × systolic blood pressure, HR × SBP), cardiac output (CO) and O<sub>2</sub> consumption (MVO<sub>2</sub>) in 15 anesthetized open chest dogs. Hypoxia (Pa<sub>o2</sub> of 30-35 mm Hg) was produced in 6 dogs with an inspired O<sub>2</sub>/N<sub>2</sub> of 200/3,000. Cardiac loading was produced in 9 dogs by administration of norepinephrine (NE, 1 µg/kg/min). Each dog acted as its own control. Baseline NADH fluorometry, <sup>31</sup>P-NMR saturation transfer and cardiac function measurements were performed simultaneously in each dog, after which the experimental interventions were made. Similar increases in HR × SBP, CO, and MVO2 which occurred during both interventions were associated with different bioenergetic responses. During NE infusion, the K<sub>f</sub> of CK increased from control; during hypoxia, the K<sub>f</sub> decreased from control (p < 0.05). Flux of PCr → ATP was significantly lower during hypoxia than during NE infusion (p < 0.05). PCr was decreased significantly during NE infusion (p < 0.05). In addition, NADH redox state increased (from baseline of 100%) during hypoxia (140 ± 10%) and decreased during NE infusion (78 ± 6%). These data indicate that the myocardial response to demand is not universally regulated by adenosine diphosphate (ADP) or redox state. In addition, metabolic regulators can induce changes related to the type of intervention irrespective of similarity of workload.