Daphne Merkus, Birgit Houweling, Marion van Vliet and Dirk J. Duncker. Contribution of K⁺_ATP channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction. Am J Physiol Heart Circ Physiol 000:H000-H000, 0000. - Previous studies have demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused only a slight impairment of myocardial O₂ supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation (via K⁺_ATP channels and adenosine) may have compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones thereby preventing a more severe impairment of myocardial O₂ balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade (8PT, 5 mg/kg, iv) and K⁺_ATP channel blockade (glibenclamide, 3 mg/kg, iv) produced similar decreases in myocardial O₂ supply in normal and MI swine. However, while the effect of glibenclamide waned in normal swine during exercise (P<0.05), it was maintained in MI swine. The effect of 8PT was maintained during exercise and was not different between normal and MI swine. Finally, in normal swine combined treatment with 8PT and glibenclamide produced a vasoconstrictor response that equaled the sum of the responses to blockade of the individual pathways. In contrast, in MI swine the vasoconstrictor response to 8PT and glibenclamide was similar to that produced by glibenclamide alone. Despite significant hemodynamic abnormalities in swine with a recent MI, myocardial O₂ supply and _O2 consumption in remodeled myocardium are still closely matched during exercise. This close matching is supported by increased K⁺_ATP channel-mediated coronary vasodilation. Although the net vasodilator influence of adenosine was unchanged in remodeled myocardium, it became exclusively dependent on K⁺_ATP channel opening.