The antihypertensive action of clonidine analogs are generally ascribed to stimulation of medullary alpha 2-adrenergic receptors. Several recent studies have implicated the newly characterized class of imidazoline receptors as playing a more important role in this regard. In this study, a series of doses of four imidazoline and two nonimidazoline antihypertensive drugs were administered by intracisternal (i.c.) injection to freely moving spontaneously hypertensive rats. All six drugs produced a dose-dependent fall in mean arterial pressure (MAP) and heart rate (HR). The most potent agents in lowering MAP were the imidazoline agents, particularly moxonidine, a drug that has high affinity for I1-imidazoline receptors, but relatively low affinity for alpha 2-adrenergic receptors. There was a high correlation between the apparent binding affinity (Ki) for I1-receptors on membranes derived from bovine rostral ventrolateral medulla and the relative potency for lowering MAP after i.c. injection in spontaneously hypertensive rats. In contrast, no correlation existed between binding affinity values for alpha 2-adrenergic receptors derived from the same source and the antihypertensive response. The results of these experiments are consistent with a role for medullary I1-imidazoline receptors in mediating the antihypertensive action of clonidine and related imidazoline compounds in conscious hypertensive animals. The nonimidazoline agent, guanfacine, although a clinically effective antihypertensive agent, was not efficacious after i.c. injection. This discrepancy may be explained by an opposing pressor action or by a depressor action mediated by alpha 2-adrenergic receptors at an alternate site when the drug is peripherally administered. In contrast, the other nonimidazoline antihypertensive agent azepexole was fully efficacious after i.c. injection of the highest doses. Further studies may be necessary to determine whether drugs such as azepexole have a receptor target other than I1 or alpha 2-adrenergic receptors. We conclude that antihypertensive efficacy within the lower brainstem of conscious animals is predicted by interaction with I1-imidazoline but not alpha 2-adrenergic receptors.