Analysis of the relationships between cardiac oxygen usage (MVO2), cardiac muscle adenosine levels ([Ado]), and coronary vascular resistance (R) in open-chest, anesthetized dogs tested the hypothesis that adenosine is a physiological regulator of coronary flow. Experiments using each dog as its own control showed that [Ado] varied directly with MVO2 as the latter changed spontaneously or in response to atrial pacing, paired pacing, aortic constriction, or β-adrenergic blockade. In turn, R varied inversely with changes in [Ado]. Stimulating MVO2with isoproterenol significantly increased the slope of the regression of [Ado] on MVO2 as well as of R"1on [Ado]. The effect of β-adrenergic stimulation on [Ado] is unexplained, but its effect on R"1seems to reflect the combined effects of adenosine and direct β-adrenergic coronary relaxation. These results support the hypothesis that adenosine mediates the coronary flow responses to changes in MVO2.Circ Res 47: 875-882, 1980