New central mediators as targets of centrally acting antihypertensive drugs

The modulation of peripheral sympathetic activity by the central nervous system may involve various pathways, neurotransmitters and receptors. In particular central catecholaminergic neurones and alpha-adrenoceptors have been analysed in detail, and they are recognized as important targets of the classic centrally acting antihypertensives clonidine, guanfacine and alpha-methyl-DOPA. Initially these drugs have been assumed to reduce elevated blood pressure via the stimulation of central alpha 2-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 involved in the central regulation of peripheral sympathetic activity, and for that matter as a 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: [formula: see text] The various compounds mentioned will thus cause peripheral sympathoinhibition, initiated by different receptor targets in the CNS. Finally, the peripheral alpha 1-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.