Coronary blood flow is controlled via several vasoactive mediators that exert their effect on coronary resistance vessel tone through activation of K⁺-channels in vascular smooth muscle. Since K⁺_Ca-channels are the predominant K⁺-channels in the coronary vasculature, we hypothesized that K⁺_Ca-channel activation contributes to exercise-induced coronary vasodilation. In view of previous observations that K⁺_ATP-channels contribute, in particular, to resting coronary resistance vessel tone, we additionally investigated the integrated control of coronary tone by K⁺_Ca- and K⁺_ATP-channels. For this purpose, the effect of K⁺_Ca-blockade with tetraethylammonium (TEA, 20 mg/kg iv) on coronary vasomotor tone was assessed in the absence and presence of K⁺_ATP-channel blockade with glibenclamide (3 mg/kg iv), in chronically instrumented swine at rest and during treadmill exercise. During exercise, myocardial O₂-delivery increased commensurately with the increase in myocardial O₂-consumption, so that myocardial O₂ extraction and coronary venous PO₂ (CVPO₂) were maintained constant. TEA (in a dose that had no effect on K⁺_ATP-channels) had little effect on the myocardial O₂-balance at rest, but blunted the exercise-induced increase in myocardial O₂-delivery, resulting in a progressive decrease of CVPO₂ with increasing exercise intensity. Conversely, glibenclamide caused a marked decrease in CVPO₂ at rest, that waned at higher exercise levels. Combined K⁺_Ca- and K⁺_ATP-channel blockade resulted in coronary vasoconstriction at rest that was similar to that caused by glibenclamide alone, and which was maintained during exercise, suggesting that K⁺_Ca- and K⁺_ATP-channels act in a linear additive fashion. In conclusion, K⁺_Ca-channel activation contributes to the metabolic coronary vasodilation that occurs during exercise. Furthermore, in swine K⁺_Ca- and K⁺_ATP- channels contribute to coronary resistance vessel control in a linear additive fashion.