Centrally acting antihypertensives: A renaissance of interest. Mechanisms and haemodynamics

Background Classic centrally acting antihypertensives are known to stimulate alpha(2)-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 alpha(2)-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, Antihypertensives Clonidine, guanfacine, guanabenz and alpha-methyldopa (via its active metabolite alpha-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 alpha(2)-adrenoceptors it is virtually impossible to separate the desired centrally induced antihypertensive effect and the adverse reactions by designing new compounds, Drug targets I-1-imidazoline receptors have recently been discovered as a new target of centrally acting antihypertensives. When stimulated with agonists the I-1-imidazoline receptors, located in the nucleus reticularis lateralis will trigger peripheral sympathoinhibition, following similar pathways as involved in the effects of the classic alpha(2)-adrenoceptor stimulants, Moxonidine and rilmenidine are I-1-imidazoline receptor stimulants with little affinity for alpha(2)-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, Conclusion Accordingly, it would now be possible to separate the attractive haemodynamic properties and the side-effects of centrally acting antihypertensives.