This study compares the coronary vasoactivity of acetate in the blood-perfused heart of the open-chest dog and in the buffer-perfused guinea-pig heart. In the dog acetate is a weak but probably fully efficacious coronary agonist. Direct intracoronary infusions of isosmolar Na acetate caused dose-dependent coronary vasodilation and decreased transcoronary O2 extraction, resulting in an increase in cardiac O2 usage of up to 40%. Acetate raised coronary flow to at least 50% above control in 63 of 67 dogs but caused maximum coronary vasodilation (400% of control) in only 39 of the 67. The frequency distribution of the acetate EC-20 decreased monotonically from a mode at <1 mM over a range extending to >6 mM, suggesting a single population of animals characterized by a rather wide range of sensitivity to acetate. Theophylline antagonized acetate vasodilation, in support of the idea that adenosine mediates the coronary effects of acetate. In the guinea-pig heart, acetate in concentrations up to 10 mM caused minimal increases in coronary flow that were completely accounted for by the small change in O2 usage that resulted from switching from glucose to acetate the main energy source. Acetate (10 mM) elicited a small release of adenosine and its degradation products.