Relationship between imidazoline and alpha2-adrenoceptors involved in the sympatho-inhibitory actions of centrally acting antihypertensive agents.

Since the first suggestion of the existence of imidazoline receptors, there has been a continuing and yet unresolved debate as to their contribution to the antihypertensive actions of clonidine-like agents. In this review we bring together a number of studies from our laboratory which have examined the importance and interdependence of imidazoline receptors and alpha2-adrenoceptors in the mechanism of action of centrally acting antihypertensive drugs. Using conscious rabbits and a range of imidazoline and specific alpha2-adrenoceptor antagonists we have consistently found that second generation agents rilmenidine and moxonidine preferentially act via imidazoline receptors but that alpha2-adrenoceptors are important for the hypotension produced by clonidine and alpha-methyldopa. Despite this difference in receptor mechanism, the hypotension produced by all these drugs is dependent on central noradrenergic pathways. In other studies using anaesthetised rabbits and direct measures of sympathetic nerve activity we confirmed the generally held view that the major site of sympatho-inhibitory actions and sympathetic baroreflex effects of centrally acting antihypertensive agents is the rostral ventrolateral medulla (RVLM). We also found, using microinjection of specific antagonists, that alpha2-adrenoceptors in this nucleus appear to be activated as a consequence of imidazoline receptor activation. Thus, there appears to be a close relationship between imidazoline receptors and alpha2-adrenoceptors located in the RVLM in mediating the hypotension and inhibition of renal sympathetic nerve activity. Furthermore in recent studies using a noradrenergic neurotoxin microinjected into the RVLM we found that this treatment selectively blocked the actions of moxonidine but not clonidine, suggesting that I1-imidazoline receptors may be located on adrenergic terminals in situ. By contrast, clonidine acts predominantly via alpha2-adrenoceptors, perhaps located on cell bodies in the nucleus. We conclude that there is indeed a close nexus between 'presynaptic' imidazoline receptors on noradrenergic terminals and 'downstream' alpha2-adrenoceptors within the RVLM. Our hypothesis brings together opposing points of view that the mechanism for hypotension must involve either the imidazoline receptor or the alpha2-adrenoceptor. Clearly both are important.