Classic centrally acting antihypertensives are known to stimulate α2-adrenoceptors located in the pontomedullary region, in the vicinity of the nucleus tractus solitarii, vasomotor centre, vagal nucleus and the various interconnecting neurones. The stimulation of these central α2-adrenoceptors induces peripheral sympathoinhibition and hence a reduction in (elevated) blood pressure, predominantly as a result of vasodilation and a consequent decrease in peripheral vascular resistance.
Clonidine, guanfacine, guanabenz and α-methyldopa (via its active metabolite α-methylnoradrenaline) are well-known examples of classic centrally acting antihypertensives. They are effective antihypertensives with an attractive haemodynamic profile. However, these agents have lost much of their clinical interest because of their subjectively unpleasant side-effects (sedation, dry mouth, impotence). Since these side-effects are also mediated, to a major extent, by α2-adrenoceptors it is virtually impossible to separate the desired centrally induced antihypertensive effect and the adverse reactions by designing new compounds.
I1-Imidazoline receptors have recently been discovered as a new target of centrally acting antihypertensives. When stimulated with agonists the I1-imidazoline receptors, located in the nucleus reticularis lateralis will trigger peripheral sympathoinhibition, following similar pathways as involved in the effects of the classic α2-adrenoceptor stimulants. Moxonidine and rilmenidine are I1-imidazoline receptor stimulants with little affinity for α2-adrenoceptors. Accordingly, such agents lower elevated blood pressure in a similar manner as the aforementioned older drugs, but it may be hoped that their side-effect profile is more favourable.
Accordingly, it would now be possible to separate the attractive haemodynamic properties and the side- effects of centrally acting antihypertensives.