From the very earliest suggestion of a distinction between imidazoline receptors and alpha2-adrenoceptors, there has been much debate as to their contribution to the antihypertensive actions of clonidine-like agents. However, with the development of drugs such as rilmenidine that are more selective for I1 imidazoline receptors, their role and also their close relationship with alpha2-adrenoceptors has become clearer. We have examined this question using a range of imidazoline and alpha2-adrenoceptor antagonists given centrally and peripherally to conscious rabbits. We found that second-generation agents such as rilmenidine preferentially act via imidazoline receptors but that alpha2-adrenoceptors are important for the hypotension produced by the first-generation agents clonidine and alpha-methyldopa. In addition to the hypotension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits cardiac sympathetic baroreflexes and diminishes the increase in renal sympathetic activity produced by environmental stress. In other studies using anesthetized rabbits and direct measures of sympathetic nerve activity, we confirmed that the major site of sympathoinhibitory actions and sympathetic baroreflex effects of rilmenidine is the rostral ventrolateral medulla. Our results also suggest that alpha2-adrenoceptors are activated as a consequence of imidazoline receptor activation by rilmenidine. Thus, though imidazoline receptors appear to be the primary target of rilmenidine, "downstream" alpha2-adrenoceptors within the brainstem are also involved and need to be considered in developing pharmacologic strategies for antihypertensive treatment involving imidazoline agents.