Effects of clonidine on central and peripheral nerve tone in primary hypertension.

Abstract

SUMMARY To define the mechanisms whereby clonidine lowers blood pressure, we measured cerebrospinal fluid and plasma levels of norepinephrine, normetanephrine, epinephrine, dopamine, and the dopamine metabolite homovanillic acid in 10 primary hypertensive subjects before and after 3 months of clonidine treatment (mean dose, 0.68 mg/day). Catecholamines were measured by radioenzymatic methods. Cerebrospinal fluid and plasma sampling was performed after subjects had fasted and remained supine overnight, and plasma sampling was repeated 2 hours later, after subjects had ambulated. Supine and upright blood pressure fell, as might be expected. Cerebrospinal fluid levels of norepinephrine and normetanephrine fell significantly, but dopamine and homovanillic acid levels were unchanged. Plasma norepinephrine, normetanephrine, and epinephrine levels decreased 30 to 50%, and supine dopamine levels also fell. The percent fall in supine blood pressure was related to the fall of cerebrospinal fluid and plasma norepinephrine. There were also positive relationships between the decreases of plasma norepinephrine and of normetanephrine and dopamine. The cerebrospinal fluid/plasma norepinephrine ratio was unaffected by clonidine, suggesting that the drug lowered both pools equally. Our findings indicate that clonidine decreases both central and peripheral norepinephrine activity. The dopaminergic activity of cerebrospinal fluid was unaffected by clonidine, and though plasma dopamine levels tended to be lower after treatment, mean plasma prolactin level, an index of dopaminergic activity, was also unchanged. The fall in plasma epinephrine level is probably related to diminished sympathetic adrenomeduilary stimulation and is unlikely to contribute to clonidine's antihypertensive action. These results also suggest that measurement of normetanephrine in cerebrospinal fluid and plasma provides a good index of norepinephrine activity. (Hypertension 8: 611-617, 1986) KEY WORDS * plasma catecholamines cerebrospinal fluid essential hypertension • effects of clonidine T HERE is evidence, albeit controversial, 1 that sympathetic nervous hyperactivity associated with raised circulating plasma catecholamine levels is involved in the pathogenesis of essential hypertension.2 " 4 Norepinephrine (NE) is the principal neurotransmitter of the sympathetic nervous system 5 and is formed locally in the nerve terminals from the amino acid tyrosine and dopamine. Clonidine is reported to lower blood pressure through central mechanisms Received April 17, 1985; accepted December 9, 1985. studies with clonidine relate to its effects on peripheral catecholamine levels. 14 " 16 Martin et al., 17 however, reported that clonidine decreased NE levels and increased levels of the dopamine metabolite homovanillic acid (HVA) in the cerebrospinal fluid (CSF) of five normotensive subjects with amnesic disorders. Cubeddu et al. 18 recently found that clonidine lowered levels of NE, but not epinephrine (E) or dopamine (DA), in the CSF and plasma of hypertensive su...

Plasma Metadrenalines: Do they Provide Useful Information about Sympatho-Adrenal Function and Catecholamine Metabolism?

“…The much lower plasma concentrations of free normetadrenaline than of noradrenaline, but higher concentrations of normetadrenaline sulphate, the age-dependence of plasma noradrenaline and nor metadrenaline, higher plasma concentrations in hypertensive than in normotensive subjects and increases in concentrations during sympathetic acti vation agree well with previous findings [9,10,[20][21][22][23][24][25]. The parallel increases in plasma normetadrena line and noradrenaline in heart failure also support the view that plasma normetadrenaline reflects sym pathetic outflow.…”

“…Other reports about the clinical utility of plasma metadrenalines for assessment of sympatho-adrenal activity are largely limited to those of DeQuattro and colleagues [9,10,[20][21][22][23], who used a radioenzymic assay to measure plasma concentrations of normetadrenaline in hypertension and during vari ous manipulations of sympathetic outflow. The radioenzymic assay depends on N-terminal méthyla tion of normetadrenaline, so that metadrenaline cannot be measured.…”

Mechanisms of a clonidine-induced decrease in portal pressure in normal and cirrhotic conscious rats

“…Clonidine significantly reduced plasma noradrenaline levels in both groups of animals, whereas saline had no effect. This reduction is consistent with the known central sympatholytic action of this drug (6,20), which produces a negative feedback of noradrenaline secretion through a2 stimulation. This effect is in agreement with that observed in cirrhotic patients (1,2) and in normal subjects (5, 6).…”

Centrally Acting Antihypertensive Agents in the Treatment of Hypertension

“…Plasma catecholamine levels fall with centrally acting therapy, which may relate, in part, to stimulation of peripherally situated presynaptic α 2 -receptors [ 10 ]. Clonidine stimulates both α 2 -receptors and imidazoline (I 1 ) receptors as the basis for its peripheral sympathoinhibition [ 11 ].…”