DOES A 2ND-GENERATION OF CENTRALLY ACTING ANTIHYPERTENSIVE DRUGS REALLY EXIST

The site of the hypotensive action of imidazoline compounds, such as c lonidine, was first identified within the rostroventrolateral part of the brainstem: the nucleus reticularis lateralis. After that, it was s hown that imidazolines and related substances reduced blood pressure w hen applied in this area whereas catecholamines were not capable of pr oducing such an effect. These data led us to suggest the existence of receptors specific for imidazoline-like compounds different from the a lpha(2)-adrenoceptors. Soon after, the existence of imidazoline bindin g sites was reported in the brain and in a variety of peripheral tissu es including the human kidney. As expected, these specific binding sit es do not bind the catecholamines. The imidazoline binding sites are a lready subclassified in two groups: the I-1-subtype sensitive to cloni dine and idazoxan, and the I-2-subtype, sensitive to idazoxan and near ly insensitive to clonidine. Functional studies confirmed that the hyp otensive effects of clonidine-like drugs involved imidazoline receptor s while their most frequent side effects only involved alpha(2)-adreno ceptors, However, recent functional evidence suggests that a cross tal k between imidazoline receptors and alpha(2)-adrenoceptors is necessar y to trigger a hypotensive effect within the ventral brainstem. Rilmen idine and Moxonidine are the leader compounds of a new class of antihy pertensive drugs selective for imidazoline receptors. At hypotensive d oses, these drugs are devoid of significant sedative effect. Rilmenidi ne evoked hypotension when injected within the nucleus reticularis lat eralis region; it competed for [H-3]-clonidine bound to specific imida zoline binding sites in human medullary membrane preparations but prov ed more selective for cerebral imidazoline receptors than clonidine. I t is suggested that this selectivity might explain the low incidence o f their side effects. Additional potentially beneficial actions on car diac arrhythmias or congestive heart failure enlarge the therapeutic i nterest of imidazoline-related drugs. Recent binding and functional da ta throw a new light on the optimal pharmacological profile of this se cond generation of centrally acting antihypertensive drugs. (C) 1998 E lsevier Science B.V. All rights reserved.