Chronic clonidine treatment and its withdrawal: Effects on blood pressure and catecholamine synthesizing enzymes in brain-stem nuclei

Atkinson, Jeffrey; Lambás‐Señas, Laura; Parker, M.; Boillat, Nicole; Luthi, P.; Sonnay, Mireille; Seccia, Michèle; Renaud, Bernard

doi:10.1016/0014-2999(86)90397-3

Cited by 18 publications

(11 citation statements)

References 30 publications

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“…Consistent with the idea that catecholamine synthesis in the central nervous system and in the periphery is differently regulated and in agreement with previous reports [26–28], we also show that the activity of tyrosine hydroxylase and catecholamine levels in the brain of spontaneously hypertensive rats was reduced after clonidine treatment. Catecholamine synthesis in spontaneously hypertensive rat brain has been shown to be decreased in the pre‐hypertensive stage and increased in hypertensive animals [29].…”

Section: Discussionsupporting

confidence: 94%

“…However, in this study, the effect of clonidine withdrawal after 4‐week treatment was not addressed. Atkinson and coworkers have previously shown that although chronic clonidine treatment improved cardiovascular parameters in 3‐month‐old spontaneously hypertensive rats, withdrawal from clonidine was marked by tachycardia and an increase in mean arterial blood pressure and in heart rate [26]. Given that in this study, we began treatment with clonidine in young normotensive spontaneously hypertensive rats, rather than hypertensive rats, the question of whether or not this treatment abolishes or attenuates the development of hypertension in spontaneously hypertensive rats remains open.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Moura

Afonso

Serrão

et al. 2009

Basic Clin Pharma Tox

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Abstract:In the present study, we evaluated the effect of the α 2 -adrenoceptor agonist clonidine on tyrosine hydroxylase activity in adrenal medulla and brain of spontaneously hypertensive rats and Wistar Kyoto rats. Six-week-old animals were treated with clonidine (100 μ g/kg body weight, daily, i.p.) for 4 weeks. Treatment with clonidine significantly reduced mean arterial blood pressure in spontaneously hypertensive rats to values similar to normotensive Wistar Kyoto rats. In the adrenal medulla of spontaneously hypertensive rats, clonidine treatment produced a significant increase in tyrosine hydroxylase activity with higher V max values and no changes in K M values. This effect was accompanied by a significant increase in tyrosine hydroxylase protein expression and of noradrenaline and adrenaline levels. In the brain of spontaneously hypertensive rats, treatment with clonidine produced a significant decrease in tyrosine hydroxylase activity with lower V max values and no changes in K M values accompanied by a significant decrease in tyrosine hydroxylase protein expression and of dopamine and noradrenaline levels. In Wistar Kyoto rats, clonidine treatment had no effect on tyrosine hydroxylase activity and protein expression or catecholamine levels in adrenal medulla or brain. Clonidine treatment significantly reduced noradrenaline and adrenaline plasma levels in spontaneously hypertensive rats and Wistar Kyoto rats. In conclusion, treatment with the α 2 -adrenoceptor agonist clonidine prevented the increase in mean arterial blood pressure in young spontaneously hypertensive rats. This effect was accompanied by opposite effects on tyrosine hydroxylase activity in spontaneously hypertensive rat adrenal medulla and brain: an increase in adrenal medulla and a decrease in brain, bringing sympathetic function to a similar profile found in normotensive Wistar Kyoto rats.The endogenous catecholamines noradrenaline and adrenaline mediate sympathetic regulation of blood pressure [1]. These effectors of the sympathetic nervous system are synthesized within sympathetic neurons and chromaffin cells of the adrenal medulla by a well-defined series of reactions that start with the conversion of tyrosine to 3,4-dihydroxyphenylalanine mediated by tyrosine hydroxylase, the initial and rate-limiting enzyme of the pathway [2]. Noradrenaline is the principal neurotransmitter of sympathetic neurons, whereas adrenaline is secreted from the chromaffin cells of the adrenal medulla into the circulation. Whereas the actions of noradrenaline are mostly restricted to the sites of release from sympathetic nerves, adrenaline acts as a neurohormone to activate cardiovascular and metabolic responses via the blood stream.Increased sympathetic nervous system activity with higher tyrosine hydroxylase activity and catecholamine levels are common features of hypertension in human beings and in the spontaneously hypertensive rat [3,4], an animal model used to investigate the mechanisms of essential hypertension [5]. It is noteworthy that in spont...

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Moura

Afonso

Serrão

et al. 2009

Basic Clin Pharma Tox

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“…The lack of change in adrenaline concentrations and in noradrenergic and dopaminergic activity within the medulla oblongatalpons (present study) and the restoration of normal adrenaline synthesis in the hindbrain (Atkinson et al 1986), however, suggests that the decreases in hypothalamic adrenaline concentrations during clonidine withdrawal may arise from alterations in synaptic processes in this brain region.…”

Section: Discussioncontrasting

confidence: 71%

“…The continuous infusion (over 10-12 days) of the centrally acting a-adrenoceptor agonist clonidine (Jarrott I 984) produces a variety of effects in normotensive and spontaneously hypertensive (SHR) rats including cardiovascular depression (Thoolen et al 198 1 a;Atkinson et a/. 1986;Lewis et al 1987), abolition of rapid eye movement sleep (Lewis et al 1984;Jarrott et al 1988) and modification of the circadian rhythm in body temperature (Maccarrone et al 1985;Lewis et al 1986).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Hypothalamic Adrenaline in the Clonidine Withdrawal Syndrome in Normotensive and Spontaneously Hypertensive Rats

Lewis

Rowe

Jarrott

1988

Clin Exp Pharma Physio

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1. The concentrations of adrenaline and other catecholamines (noradrenaline and its major metabolite DHPG, dopamine and its major metabolite DOPAC) were measured in the hypothalamus and medulla oblongata of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) which had received a continuous subcutaneous infusion of clonidine (10 micrograms/kg per h) for 10 days, and also in WKY and SHR rats which were killed 15-18 h after the cessation of the 10-day infusion. 2. The concentrations of adrenaline in the hypothalamus and medulla oblongata/pons of the clonidine treated WKY and SHR rats were not different from their respective controls. However, the adrenaline concentrations in the hypothalamus (but not the medulla oblongata) were significantly decreased in the post-infusion WKY and SHR. 3. These results suggest that hypothalamic adrenergic mechanisms may have a common involvement in the post-clonidine infusion syndromes displayed by the WKY and SHR strains.

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“…There are, however, interesting studies regarding Ca 2÷ channel blockers, verapamil and nimodipine, prevent naloxone precipitated modifications in norepinephrine and its metabolites in morphine-dependent rats (Bongianni et al 1986). In addition, clonidine withdrawal, which accompanies the changes in the activities of tyrosine hydroxylase and dopamine-fi-hydroxylase in some areas of the brain (Distefano et al 1980;Atkinson et al 1986), has also been reported to be inhibited by Ca 2÷ blockers (Barrios et al 1993). These results suggest that Ca > channels might be related to the change in catecholamines, including DA.…”

Section: Discussionmentioning

confidence: 95%

Effects of diltiazem, a Ca2+ channel blocker, on naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats

Tokuyama

1996

Psychopharmacology

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The effects of diltiazem, an L-type Ca2+ channel blocker, on naloxone (an opioid receptor antagonist)-precipitated withdrawal signs and changes in extracellular levels of dopamine (DA) and its metabolites in various brain regions of morphine (a mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa mixed opioid receptor agonist) dependent rats were investigated using high performance liquid chromatography fitted with an electrochemical detector (HPLC-ED). Rats were rendered opioid-dependent by continuous intracerebroventricular (i.c.v.) infusion with morphine (26 nmol/microliters per h) or butorphanol (26 nmol/microliters per h) for 3 days. The expression of physical dependence produced by these opioids, as evaluated by naloxone (5 mg/kg. i.p.)-precipitated withdrawal signs, was reduced by concomitant infusion of diltiazem (10 and 100 nmol/microliters per h). Under the same condition, naloxone decreased the levels of: DA in the cortex, striatum, and midbrain; 3,4-dihydroxyphenylacetic acid (DOPAC) in the cortex, striatum, limbic areas, and midbrain: and homovanilic acid (HVA) in the striatum, limbic areas, and midbrain regions. In animals rendered dependent on butorphanol, the results obtained were similar to those of morphine-dependent rats except for the changes in DOPAC levels. Furthermore, concomitant infusion of diltiazem and opioids blocked the decreases in levels of DA, DOPAC, and HVA in a dose-dependent manner. These results suggest that the augmentation of intracellular Ca2+ mediated through L-type Ca2+ channels during continuous opioid infusion results in a decrease in extracellular levels of DA and its metabolites in some specific regions, which are intimately involved in the expression of withdrawal syndrome precipitated by naloxone.

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Chronic clonidine treatment and its withdrawal: Effects on blood pressure and catecholamine synthesizing enzymes in brain-stem nuclei

Cited by 18 publications

References 30 publications

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Effect of Clonidine on Tyrosine Hydroxylase Activity in the Adrenal Medulla and Brain of Spontaneously Hypertensive Rats

Involvement of Hypothalamic Adrenaline in the Clonidine Withdrawal Syndrome in Normotensive and Spontaneously Hypertensive Rats

Effects of diltiazem, a Ca2+ channel blocker, on naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats

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