Modulation of sympathetic outflow by centrally acting antihypertensive drugs.

van Zwieten PA

Department of Pharmacotherapy, Academic Medical Center, University of
Amsterdam, the Netherlands.

The modulation of peripheral sympathetic activity by the central nervous system
(CNS) has been intensely investigated as a potential target of antihypertensive
drugs. In particular, clonidine, guanfacine, and alpha-methyl-DOPA (acting via
its metabolite alpha-methylnoradrenaline) have been developed as
antihypertensives with a predominantly CNS site of action. Initially these
drugs have been assumed to reduce elevated blood pressure via the stimulation
of central alpha2-adrenoceptors in the brain stem, thus leading to peripheral
sympathoinhibition and a reduction of elevated blood pressure, heart rate, and
plasma catecholamines. In a later stage it has been recognized that central
imidazoline (I1) receptors, probably located in the nucleus reticularis
lateralis in the medullary region, may also be the target of centrally acting
antihypertensives. Moxonidine and rilmenidine are the prototypes of such
agents. Accordingly, the receptor profile of the various types of centrally
acting antihypertensives may be characterized as follows: alpha-methyl-DOPA,
alpha2 (through alpha-methylnoradrenaline); clonidine alpha2 + I1 (mixed
agonist); and moxonidine, rilmenidine, I1 > alpha2. The various compounds
mentioned will thus cause peripheral sympathoinhibition, initiated by different
receptor targets in the CNS. Finally, the peripheral alpha1-blocker, urapidil,
has been demonstrated to possess an additional central mechanism, mediated by
the stimulation of serotonergic 5HT1A-receptors located in the rostral
ventrolateral medulla. The stimulation of these 5HT1A-receptors appears to
suppress, via the autonomic nervous system, the reflex tachycardia triggered by
vasodilation.