Effects of drugs on precapillary vessels and oxygen uptake may differ from effects on resistance vessels and total flow in skeletal muscle. This study was performed to compare effects of phentolamine and isoproterenol, two drugs which are used to treat shock, on oxygen uptake in skeletal muscle. Oxygen uptake of gracilis muscle (GVO2) was measured in muscles perfused at constant flow or constant pressure in normotensive dogs. We compared effects of the drugs on oxygen uptake at doses chosen so that both drugs produced comparable effects on vascular resistance. With flow constant, phentolamine increased but isoproterenol decreased or did not alter GVO2. With constant pressure, phentolamine produced significantly greater increases in GVO2. For example, increases in GVO2 occurred with all three doses of phentolamine, but only with the high dose of isoproterenol. Neither drug altered oxygen-hemoglobin affinity of red blood cells or oxygen consumption of skeletal muscle in vitro. The results suggest that phentolamine produces more favorable effects than isoproterenol on oxygen uptake in skeletal muscle, presumably because of greater dilator action on precapillary sphincters.