Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats

doi:10.1016/0014-2999(76)90196-5

European Journal of Pharmacology

Volume 38, Issue 1, July 1976, Pages 19-22

https://doi.org/10.1016/0014-2999(76)90196-5 Get rights and content

Abstract

Bilateral electrolytic lesion of the area of the nucleus tractus solitarii (NTS) in rats produced a sustained increase in blood pressure and reduced the hypotensive response to a single dose of clonidine (30 μg/kg, i.v.). The same dose of clonidine evoked a much larger drop in blood pressure in another group of rats in which an equivalent increase in blood pressure was produced by bilateral section of the vagosympathetic trunks and occlusion of both carotid arteries. It is concluded that the dorsal part of the medulla oblongata in the area of NTS is an important link in the hypotensive action of clonidine.

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Cited by (23)

GABA mechanisms of the nucleus of the solitary tract regulates the cardiovascular and sympathetic effects of moxonidine
2016, Autonomic Neuroscience: Basic and Clinical
Citation Excerpt :
Many brainstem, spinal cord and forebrain regions have been suggested to be crucial where clonidine or moxonidine-like drugs influence the autonomic nervous system (Isaac, 1980; Head et al., 1998; Totola et al., 2013). The NTS and RVLM/C1 regions are the main sites of action of these drugs (Lipski et al., 1976; Bousquet et al., 1981; Dominiak, 1994; Guyenet, 1997; Ernsberger et al., 1997; Hayar and Guyenet, 2000; Totola et al., 2013). The latter is considered to be the main region that sends sympathetic efferent projections to spinal cord and has been shown to contain imidazoline (I1R) receptors as well as α2-AR (Kino et al., 2005).
The antihypertensive drugs moxonidine and clonidine are α₂-adrenoceptor and imidazoline (I₁) agonists. Previous results from our laboratory have shown that moxonidine can act in the commissural nucleus of the solitary tract (commNTS). In addition, some studies have shown that GABA or glutamate receptor blockade in the RVLM blunted the hypotension produced by these antihypertensive agents in spontaneously hypertensive rats. Therefore, in the present study we verify whether the cardiovascular and sympathetic effects produced by moxonidine in the commNTS are dependent on GABAergic or glutamatergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethane-anesthetized, and artificially-ventilated male Wistar rats (250–350 g). Injection of the GABAA antagonist bicuculline (25 pmol/50 nL) into the commNTS reduced the hypotension as well as the sympathoinhibition elicited by moxonidine. Prior injection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/50 nL) into the commNTS was not effective in reducing the hypotension and sympathoinhibition elicited by moxonidine. Therefore, we conclude that the hypotensive and sympathoinhibitory effects elicited by microinjection of moxonidine into the commNTS are dependent on GABA receptors, but not ionotropic glutamate receptors.
Relationship between imidazoline and α<inf>2</inf>-adrenoceptors involved in the sympatho-inhibitory actions of centrally acting antihypertensive agents
1998, Journal of the Autonomic Nervous System
Since the first suggestion of the existence of imidazoline receptors, there has been a continuing and yet unresolved debate as to their contribution to the antihypertensive actions of clonidine-like agents. In this review we bring together a number of studies from our laboratory which have examined the importance and interdependence of imidazoline receptors and α₂-adrenoceptors in the mechanism of action of centrally acting antihypertensive drugs. Using conscious rabbits and a range of imidazoline and specific α₂-adrenoceptor antagonists we have consistently found that second generation agents rilmenidine and moxonidine preferentially act via imidazoline receptors but that α₂-adrenoceptors are important for the hypotension produced by clonidine and α-methyldopa. Despite this difference in receptor mechanism, the hypotension produced by all these drugs is dependent on central noradrenergic pathways. In other studies using anaesthetised rabbits and direct measures of sympathetic nerve activity we confirmed the generally held view that the major site of sympatho-inhibitory actions and sympathetic baroreflex effects of centrally acting antihypertensive agents is the rostral ventrolateral medulla (RVLM). We also found, using microinjection of specific antagonists, that α₂-adrenoceptors in this nucleus appear to be activated as a consequence of imidazoline receptor activation. Thus, there appears to be a close relationship between imidazoline receptors and α₂-adrenoceptors located in the RVLM in mediating the hypotension and inhibition of renal sympathetic nerve activity. Furthermore in recent studies using a noradrenergic neurotoxin microinjected into the RVLM we found that this treatment selectively blocked the actions of moxonidine but not clonidine, suggesting that I₁-imidazoline receptors may be located on adrenergic terminals in situ. By contrast, clonidine acts predominantly via α₂-adrenoceptors, perhaps located on cell bodies in the nucleus. We conclude that there is indeed a close nexus between `presynaptic' imidazoline receptors on noradrenergic terminals and `downstream' α₂-adrenoceptors within the RVLM. Our hypothesis brings together opposing points of view that the mechanism for hypotension must involve either the imidazoline receptor or the α₂-adrenoceptor. Clearly both are important.
Central action of α-adrenoceptor agents on the baroreceptor reflex
1992, Journal of the Autonomic Nervous System
In chloralose-anaesthetized cats the effects of intravenous application of the α₁- and α₂-adrenoceptor agonistic and antagonistic agents methoxamine, prazosin, B-HT 933 and rauwolscine were tested on baroreceptor reflex, sympathetic background activity and blood pressure. Sympathetic activity was recorded from the renal nerve and the efficacy of the central transmission of the baroreceptor reflex was measured by the duration of the complete inhibition of renal nerve activity during electrical stimulation of the left carotid sinus nerve. All baroreceptors were denervated by sectioning both carotid sinus and vagal nerves. The α₁-agonist methoxamine increased baroreceptor-induced sympathoinhibition, sympathetic background activity and blood pressure. The α₁-antagonist prazosin had the opposite effects. The α₂-agonist B-HT 933 was most effective in augmenting the inhibitory response in sympathetic activity to baroreceptor stimulation; sympathetic background activity and blood pressure were also decreased. At low doses (50 μg/kg) the α₂-antagonist rauwolscine reduced the baroreceptor sympathetic reflex inhibition and increased sympathetic activity and blood pressure. The effect of B-HT 933 upon the baroreceptor reflex could be completely antagonized by rauwolscine. These findings demonstrate a very effective facilitation of the baroreceptor reflex transmission by stimulation of central α₂-adrenoceptors. Through such humoral-neuronal interaction circulating catecholamines are likely to modulate cardiovascular control.
Ventrolateral medullary pressor area: site of hypotensive action of clonidine
1987, Brain Research
Intravenous injections of clonidine produce an initial transient increase in blood pressure followed by a long-lasting hypotension and bradycardia. The initial pressor response is due to activation of vascularα₁-adrenergic receptors while the hypotension and bradycardia are caused by the central actions of clonidine. Although, hypothalamus, nucleus tractus solitarius (NTS), ventrolateral medulla and the intermediolateral cell column of the thoracolumbar spinal cord (IML) have been implicated, the exact site of these actions of clonidine in the central nervous system is not established. The results of this investigation suggest that the pressor area in the ventrolateral medulla (VLPA) is the site of hypotensive and bradycardic actions of intravenously administered clonidine. This conclusion is based on the observation that microinjections of idazoxan, a specificα₂-adrenergic receptor blocker, into the VLPA prevented and reversed the hypotension and bradycardia despite the fact that other proposed sites of these actions (NTS, hypothalamus and IML) were intact and accessible to intravenously administered clonidine.
Clonidine can lower blood pressure by inhibiting vasopressin release
1985, European Journal of Pharmacology
The effect of clonidine on vasopressin release was studied in chloralose anesthetized rats which were made hypertensive by bilateral electrons of the nucleus tractus solitarii (NTS). NTS lesions elevated arterial pressure and plasma vasopressin levels, and both of these variable were returned toward baseline values by intravenous injection of clonidine (30 μg/kg). Furthermore, the ability of a vasopressin antagonist to lower arterial pressure in NTS hypertensive rats was markedly attenuated by clonidine treatment. In contrast, autonomic blockade (chlorisondamine, 2.5 mg/kg) in NTS lesioned rats did not reduce plasma vasopressin levels or the effect of the vasopressin antagonist on blood pressure. These data demonstrate that part of the antihypertensive effect of clonidine in NTS hypertensive rats is due to inhibition of vasopressin release into the circulation.
Effects of Clonidine, α-Methyldopa and Hydralazine on Met-Enkephalinergic Neurons in Cerebral Nuclei of Spontaneously Hypertensive Rats
1985, Japanese Journal of Pharmacology
Immunocytofluorescent and microautoradiographic methods were applied to measure met-enkephalin-like immunoreactivity (MELI) and ME receptor binding (MERB) levels in cerebral nuclei of serial brain slices from SHR which received clonidine, β-methyldopa and hydralazine at equivalent hypotensive doses. All three drugs increased both MELl and MERB levels in the caudal part of the n. tractus solitarii and its functionally related dorsomedullary nuclei and decreased them in the n. accumbens septi, in accordance with the correspondent change in glucose utilization rates in these nuclei as reported previously. Both CNS-active agents (not hydralazine) also increased MELl and MERB levels in the n. intercalatus and substantia grisea centralis, and they decreased them in the n. ventromedialis hypothalami. Differences in both CNS-active agents were minor. Vasodilative hydralazine alone decreased these levels both in the n. reticularis medialis and n. tegmenti ventralis, and it increased them slightly in the area lateralis hypothalami. The present studies indicate that ME neurons of these dorsomedullary and supramedullary nuclei may act as direct as well as homeostatic controls of blood pressure.

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^☆: This investigation was supported by Grant No. 0.9.4.1. of the Polish Academy of Sciences.

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Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats☆

Abstract

European J. Pharmacol.

European J. Pharmacol.

Brain Res.

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

European J. Pharmacol.

Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons

Acta Physiol. Scand.

Role of noradrenaline and serotonin in the control of blood pressure in normotensive and spontaneously hypertensive rats

Arch. Intern. Pharmacodyn.