The alpha-1 and alpha-2 adrenergic effects of cirazoline were evaluated in guinea-pig aorta and field-stimulated guinea-pig ileum, respectively. Cirazoline was found to be a full agonist at alpha-1 receptors having an ED50, dissociation constant (KA) and relative efficacy similar to that of (-)-norepinephrine. In contrast, cirazoline does not possess agonist activity at presynaptic alpha-2 receptors in the guinea-pig ileum. Thus, whereas norepinephrine and cirazoline both inhibited the twitch response of the field-stimulated ileum, only the response to norepinephrine was blocked by the selective alpha-2 antagonist, yohimbine. The nonadrenergic inhibition of the twitch response observed in the ileum with cirazoline resulted from weak anticholinergic activity (antimuscarinic) at the level of the postsynaptic effector organ and was observed only at high concentrations. At concentrations far below the level required to inhibit the twitch response, cirazoline was found to competitively antagonize the alpha-2-mediated inhibition of the twitch response elicited by norepinephrine. A Schild plot analysis indicated that cirazoline is a potent competitive alpha-2 receptor antagonist characterized by a pA2 value (i.e., -log KB) of 7.56. These results indicate that cirazoline is unique among imidazolines in that it is a potent alpha-1 adrenergic receptor agonist and an even more potent alpha-2 receptor antagonist. This unusual combination of activities could make cirazoline a particularly effective vasoconstricting agent.