From the very earliest suggestion of a distinction between imidazoline rece
ptors and a,adrenoceptors, there has been much debate as to their contribut
ion to the antihypertensive actions of clonidine-like agents. However, with
the development of drugs such as rilmenidine that are more selective for I
, imidazoline receptors, their role and also their close relationship with
a,adrenoceptors has become clearer. We have examined this question using a
range of imidazoline and alpha(2)-adrenoceptor antagonists given centrally
and peripherally to conscious rabbits. We found that second-generation agen
ts such as rilmenidine preferentially act via imidazoline receptors but tha
t alpha(2)-adrenoceptors are important for the hypotension produced by the
first-generation agents clonidine and a-methyldopa. In addition to the hypo
tension, rilmenidine facilitates cardiac vagal baroreflexes and inhibits ca
rdiac sympathetic baroreflexes and diminishes the increase in renal sympath
etic activity produced by environmental stress. In other studies using anes
thetized rabbits and direct measures of sympathetic nerve activity, we conf
irmed that the major site of sympathoinhibitory actions and sympathetic bar
oreflex effects of rilmenidine is the rostral ventrolateral medulla. Our re
sults also suggest that alpha(2)-adrenoceptors are activated as a consequen
ce of imidazoline receptor activation by rilmenidine. Thus, though imidazol
ine receptors appear to be the primary target of rilmenidine, "downstream"
alpha(2)-adrenoceptors within the brainstem are also involved and need to b
e considered in developing pharmacologic strategies for antihypertensive tr
eatment involving imidazoline agents. (C) 2000 American Journal of Hyperten
sion, Ltd.