The effects of midazolam on atrial rate and contractile force in the isolated canine atrium perfused with donor blood were investigated. When midazolam in a dose range of 100-1000 micrograms was injected directly into the sinus node artery of the isolated atrium, biphasic (negative followed by positive) chronotropic and triphasic (positive, negative followed by positive) inotropic effects were induced. After propranolol or imipramine, the positive chronotropic and the secondary positive inotropic effects were significantly suppressed, but the initial positive inotropic effect was not affected. Tetrodotoxin, atropine, or R05-4864, a selective ligand for peripheral benzodiazepine binding sites, did not modify midazolam-induced effects. When midazolam in a dose of 0.1-1 mg/kg was administered intravenously to the donor dog, monophasic negative chronotropic and inotropic effects in the isolated atrium were observed but were not as prominent. We conclude that midazolam has direct cardiac inhibitory properties including catecholamine release due to a tyramine-like action.