Activation of peripheral cannabinoid CB(1) receptors elicits hypotension. Using the radioactive microsphere technique, we examined the effects of cannabinoids on systemic hemodynamics in anesthetized rats. The potent cannabinoid CB(1) receptor agonist HU-210 ([-]-11-OH-Delta(9) tetrahydrocannabinol dimethylheptyl, 10 microg/kg i.v.) reduced mean blood pressure by 57+/-5 mm Hg by decreasing cardiac index from 37+/-1 to 23+/-2 ml/min/100 g (P<0.05) without significantly affecting systemic vascular resistance index. HU-210 elicited a similar decrease in blood pressure following ganglionic blockade and vasopressin infusion. The endogenous cannabinoid anandamide (arachidonyl ethanolamide, 4 mg/kg i.v.) decreased blood pressure by 40+/-7 mm Hg by reducing systemic vascular resistance index from 3.3+/-0.1 to 2.3+/-0.1 mm Hg min/ml/100 g (P<0.05), leaving cardiac index and stroke volume index unchanged. HU-210, anandamide, and its metabolically stable analog, R-methanandamide, lowered vascular resistance primarily in the coronaries and the brain. These vasodilator effects remained unchanged when autoregulation was prevented by maintaining blood pressure through volume replacement, but were prevented by pretreatment with the cannabinoid CB(1) receptor antagonist SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl]-4-methyl-1H-pyrazole-3-carboxamide HCl; 3 mg/kg i.v.). Only anandamide and R-methanandamide were vasodilators in the mesentery. We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite. Differences between the hemodynamic profile of various cannabinoids may reflect quantitative differences in cannabinoid CB(1) receptor expression in different tissues and/or the involvement of as-yet-unidentified receptors.