We have previously demonstrated that positron emission tomography (PET) with [11C]acetate allows noninvasive regional quantification of myocardial oxidative metabolism. To assess the metabolic response of normal myocardium to increased work (oxidative metabolic reserve), clearance of myocardial 11C activity after administration of [11C]acetate i.v. was measured with PET in seven normal subjects at rest and during dobutamine infusion. At rest, clearance of 11C was monoexponential and homogeneous. The rate constant of the first phase of 11C clearance, k1, averaged 0.054 +/- 0.014 min-1 at a rate-pressure produce (RPP) of 7329 +/- 1445 mmHg X bpm. During dobutamine infusion, RPP increased by an average of 141% to 17,493 +/- 3582 mm Hg Z bpm. Clearance of 11C became biexponential and remained homogeneous. k1 averaged 0.198 +/- 0.043 min-1 with a mean coefficient of variation of 16%.. k1 and RPP correlated closely (r = 0.91; p less than 0.001), and the slope of the k1/RPP relation remained consistent in all subjects (1.48 +/- 0.42). These findings suggest that PET with [11C]acetate and dobutamine stress may provide a promising approach for evaluation of regional myocardial oxidative metabolic reserve in patients with cardiac diseases of diverse etiologies and for assessment of the efficacy of interventions designed to enhance the recovery of metabolically comprised myocardium.