At steady state, a balance is expected between net myocardial uptake of the principal exogenous carbon substrates and the rate at which these substrates are metabolized. Such a balance is present when the sum of the oxygen extraction ratios (OERs) for glucose, lactate, and free fatty acids (FFA) is near unity. We have previously observed that systemic administration of the -adrenergic agonist isoproterenol (Iso) induces a state of excess myocardial substrate uptake relative to the rate of substrate metabolism, reflected by a sum of OERs significantly >1.0. This occurs in conjunction with an Iso-stimulated increase in circulating insulin levels. The goal of the present study was to determine whether this excess substrate uptake depends on the effects of insulin and time. In open-chest anesthetized pigs, myocardial blood flow, substrate uptake, and oxygen consumption were measured at baseline and during systemic administration of Iso (0.08 µg · kg¹ · min¹ iv) under the following conditions: group 1 (n = 10), normal endogenous insulin release; group 2 (n = 10), inhibition of endogenous insulin release with somatostatin; group 3 (n = 7), at 45 and 90 min Iso; group 4 (n = 7), at 45 and 90 min Iso, with exogenous insulin given during the latter measurement. In group 1, plasma insulin rose fivefold with Iso while the sum of the OERs for glucose, lactate, and FFA increased from 0.92 ± 0.21 at baseline to 1.57 ± 0.17 with Iso (P < 0.01). In group 2, somatostatin blunted the increase in insulin with Iso and there was no significant change in the sum of OERs between baseline and Iso. In group 3, the sum of OERs increased from 0.95 ± 0.11 at baseline to 1.69 ± 0.20 at 45 min Iso (P < 0.01), similar to the response of group 1. However, the state of excess substrate uptake was transient; by 90 min Iso the sum of OERs declined to 0.69 ± 0.21 (P < 0.05 vs. 45 min Iso). In group 4, excess substrate uptake could not be sustained at 90 min Iso despite administration of exogenous insulin. Systemic -adrenergic stimulation causes a transient condition of myocardial substrate uptake in excess of metabolism. Increased plasma insulin is necessary to produce this condition, but a high insulin level does not prolong the condition.