The effects of monensin on coronary blood flow (CBF) and other hemodynamic parameters were studied in anesthetized dogs. A dose-response relationship was established, and it was found that the lowest doses of monensin (5–25 μg/kg) produced a dose-dependent increase (3–5x) in CBF with a concomitant decrease in total peripheral resistance (TPR). Pretreatment with diphenhydramine, atropine, indomethacin, or propranolol resulted in no reduction in peak increase in CBF or in the duration of response to monensin. However, the response was partially blocked by aminophylline. Large doses (100 and 200 μg/kg) produced a dose-dependent increase in cardiac output, aortic pressure, and LV dP/dt max. The duration of these effects was dose-dependent, ranging from 60 to 120 min or longer. Heart rate remained unchanged with all doses of monensin. Pretreatment with propranolol, H87/07 (a cardioselective β-blocker), and D-600 given alone or in combination significantly reduced, but did not completely abolish, the monensin-induced increase in LV dP/dt max and aortic pressure responses. The increase in CBF in the left anterior descending coronary artery was not significantly affected by these drug pretreatments. Thus, our studies indicate that monensin has two distinct pharmacological effects—in the lower dose range (< 25 μg/kg) it produces a direct relaxation of the blood vessels resulting in an increase in CBF and a decrease in TPR: at high doses (> 25 μg/kg) it increases myocardial contractility and aortic blood pressure.