Central α-adrenergic systems as targets for hypotensive drugs

• Central catecholaminergic nerves have an integral place in the central connections of the autonomic nervous system, and they play an important role in the regulation of arterial blood pressure (1-19). Some evidence suggests that central serotonergic nerves also participate in the control of blood pressure (19-24). Studies in various models of experimental hypertension have demonstrated changes in the metabolism and the activity of these central monoaminergic nerves (3, 9, 13, 24). In addition, selective ablation of central catecholaminergic or serotonergic nerves with a variety of chemical compounds profoundly modifies the development of high blood pressure in a number of experimental models (7, 8, 10, 11, 17, 23, 24). It seems clear that central monoaminergic systems participate in the regulation of normal blood pressure and that their function is altered in experimental hypertension. However, the exact significance of these changes in experimental hypertension has not been established. Moreover, it is not yet clear which changes are of primary causal importance and which are secondary in nature. The development of histochemical fluorescence methods for cellular localization of biogenic amines has facilitated the mapping of specific catecholaminergic and serotonergic tracts in the central nervous system (CNS) (25-27). During the last decade it was widely held that only two catecholamines were important neurotransmitters in the CNS—dopamine in the basal ganglia and limbic systems and norepinephrine more diffusely. There is now good evidence from new immunohistochemical methods (28) and sensitive biochemical assays (29) that epinephrine is also a central neurotransmitter. Since many of the studies on brain amines and blood pressure regulation have not differentiated between dopamine, norepinephrine, and epi-

Brain amines and models of experimental hypertension.

Inhibition of adrenergic neurotransmission by clonidine: An action on prejunctional α-receptors

1. α-Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of α-methyldopa, whilst intravenous 6-hydroxydopamine reduced but did not prevent the hypotension.

2. The hypotensive effect of α-methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 μg/rat).

3. Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with α-methyldopa (300 mg/kg i.p.).

4. Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with α-methyldopa. Furthermore, α-methylnoradrenaline was found to have one-eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation.

5. Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with α-methyldopa. FLA-63, a selective dopamine-β-hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by α-methyldopa.

6. Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3-4 h after the injection of α-methyldopa (100 mg/kg i.v.).

7. These results strongly suggest that the central actions of α-methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.

G. Heyd

Papers

Central effects of sympathomimetic amines on the blood pressure.