Modulation of sympathetic outflow by centrally acting antihypertensive drugs

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.