Chronic Clonidine Treatment Research Articles

PS-B10-1: DIFFERENT MECHANISMS OF BLOOD PRESSURE REDUCTION INDUCED BY CHRONIC PERORAL OR INTRACEREBROVENTRICULAR CLONIDINE ADMINISTRATION IN SALT-DEPENDENT OR ANGIOTENSIN II-DEPENDENT HYPERTENSION

Objective: The agonists of alpha2-adrenergic receptors are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or high-renin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (PO) or intracerebroventricular (ICV) clonidine treatment. Design and Methods: Adult male Dahl S rats fed 4% NaCl diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day PO) or via the infusion into the lateral brain ventricle (0.1 mg/kg/day ICV) for 4 weeks. Basal BP as well as the contributions of renin-angiotensin system or sympathetic nervous system (acute BP responses to intravenous injection of either captopril 10 mg/kg or pentolinium 5 mg/kg) to BP maintenance were determined in conscious cannulated rats at the end of the study. Results: Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin-dependent vasoconstriction in Ren- transgenic rats, whereas it lowered residual BP in Dahl rats. Conclusions: Our results indicate different mechanisms of antihypertensive action of clonidine depending on the route of its administration - central or systemical

Effect of chronic clonidine treatment on transmitter release from sympathetic varicosities of the guinea-pig vas deferens.

1. Previous studies have demonstrated that chronic pre-synaptic inhibition of transmitter release by morphine evokes a counter-adaptive response in the sympathetic nerve terminals that manifests itself as an increase in transmitter release during acute withdrawal. In the present study we examined the possibility that other pre-synaptically acting drugs such as clonidine also evoke a counter-adaptive response in the sympathetic nerve terminals. 2. In chronically saline treated (CST) preparations, clonidine (0.5 microM) completely abolished evoked transmitter release from sympathetic varicosities bathed in an extracellular calcium concentration ([Ca(2+)](o)) of 2 mM. The inhibitory effect of clonidine was reduced by increasing [Ca(2+)](o) from 2 to 4 mM and the stimulation frequency from 0.1 to 1 Hz. 3. The nerve terminal impulse (NTI) was not affected by concentrations of clonidine that completely abolished evoked transmitter release. 4. Sympathetic varicosities developed a tolerance to clonidine (0.5 microM) following 7-9 days of chronic exposure to clonidine. 5. Acute withdrawal of preparations following chronic clonidine treatment (CCT) resulted in a significant (P < 0.005) enhancement of neurotransmitter release (3.75 times) above control levels observed in CST preparations. 6. The present findings demonstrate an enhancement of neurotransmitter release from sympathetic varicosities following acute withdrawal from chronic clonidine treatment.

The role of excitatory amino acids in the expression of precipitated acute and chronic clonidine withdrawal: an in vivo voltammetric study in the rat locus coeruleus

It has been previously shown that activation of excitatory amino acid (EAA) pathways contributes to hyperactivity of the locus coeruleus (LC) in antagonist precipitated opioid withdrawal. In this study, using differential normal pulse voltammetry to monitor catechol oxidation as an index of the activity of the LC, the role of EAA pathways in antagonist precipitated withdrawal after acute and chronic clonidine treatment was examined. Intracerebroventricular clonidine (10 μg i.c.v.) significantly reduced LC activity to 54.4 ± 3.1% of baseline 45 minutes following the injection. Subsequent systemic injection of the selective α 2 receptor antagonist atipamezole (0.2 mg/kg i.v.) or vohimbine (0.5 mg/kg i.v.) resulted in a rapid reversal of the depressant effects and a significant increase in LC activity above baseline. Pretreatment with the non-selective EAA receptor antagonist γ- d-glutamylglycine (DGG) (50 μg i.c.v.) attenuated the atipamezole-induced rebound response of the LC but not the reversal of clonidine action. However, both the yohimbine-induced rebound and reversal of clonidine effects were attenuated by DGG treated animals. In chronic clonidine treated animals (2, 5, 7, 10 μg/h i.c.v., 5 days), a challenge with atipamezole (0.2 mg/kg i.v.) produced an immediate increase in LC activity, blood pressure and heart rate. The magnitude of these responses was dependent on the dose of clonidine. The atipamezole-induced increase in LC activity and blood pressure was significantly attenuated by pretreatment with DGG (200 μg i.c.v.). These findings suggest that LC hyperactivity and blood pressure increases elicited during clonidine withdrawal are mediated in part by activation of EAA receptors. In this regard, the mechanisms underlying clonidine withdrawal closely resembles those underlying opioid withdrawal.

Effect of prolonged administration of clonidine on [ 3H]PN 200-110 and [ 125I]ϵ-conotoxin binding in mouse brain

The effect of chronic exposure to clonidine or morphine on clonidine- and morphine-induced analgesia in mice was examined. Binding of L- or N-type calcium channel antagonist to cortical membrane fractions was also compared between these groups of mice. A decrease in the analgesic effect of clonidine and morphine was observed following prolonged administration of clonidine or morphine. Binding of [ 3H]PN 200-110, an L-type calcium channel antagonist, decreased following prolonged administration of clonidine whereas it increased after morphine treatment. On the other hand, a significant increase of [ 125I]ϵ-conotoxin, an N-type calcium channel antagonist, binding was observed after chronic clonidine or morphine treatment. These results will be discussed in relation with the possible development of cross-tolerance between clonidine and morphine through the change in calcium channels, more specifically in N-type channels.

P-427 - Chronic clonidine treatment and its withdrawal: Effects on penile erection and ejaculation in the dog

P-427 - Chronic clonidine treatment and its withdrawal: Effects on penile erection and ejaculation in the dog

Chronic clonidine treatment and its termination: Effects of penile erection and ejaculation in the dog

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 μg/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.

Acute versus chronic clonidine treatment effects on conflict behavior in the rat

The present study examined the effects of acute and chronic treatment with the alpha-2-adrenoceptor agonist clonidine on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anti-anxiety treatments. In daily 10-min sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25mA). Electrification was signalled by a tone. Within 3-4 weeks of 4 day/week CSD sessions, control (i.e. non-drug) CSD behavior had stabilized (approximately 40 shock/session and 11ml water/session). Acute treatment with clonidine across a range of doses (1.25-40µg/kg; 10-min pretreatment) did not exert an anti-conflict effect, with doses greater than 5µg/kg significantly depressing unpunished responding (i.e. water intake). Similarly, administration of a single dose of clonidine (40µg/kg) across a range of pretreatment times (10 to 120min) failed to increase punished responding. In contrast, chronic post-test treatment with clonidine (40µg/kg, twice daily for 18 weeks) resulted in a dramatic and time-dependent increase in punished responding, with a latency to onset of approximately 3-4 weeks. The response to an acute challenge with chlordiazepoxide (10mg/kg) or the benzodiazepine antagonist Ro 15-1788 (4.0mg/kg) did not differ in chronic clonidine-versus saline-treated subjects, indicating that benzodiazepine receptor sensitivity had not been affected by this chronic clonidine treatment. An acute challenge with a low dose of clonidine (10µg/kg) decreased punished and unpunished responding in chronic clonidine- or saline-treated subjects. Finally, an acute challenge with the alpha-2-antagonist yohimbine (1.25mg/kg) failed to block the increase in punished responding associated with chronic clonidine treatment, indicating that the anti-conflict effect of this chronic post-test clonidine treatment was not the result of alpha-2-adrenoceptor activation at the time of CSD testing (i.e. not due to drug accumulation). Discontinuation of chronic clonidine treatment resulted in a decline to near saline-treated levels of punished responding over the course of 3 weeks of conflict testing. The relationship of these findings to the anti-anxiety effects of clonidine in humans are discussed.

Effect of Chronic Clonidine Treatment on Urinary Growth Hormone Excretion and Linear Growth in Children with Short Stature

Eleven prepubertal children with short stature were treated with clonidine (0.15 mg/m2 daily) for a period of 1 year. The effect of this drug was evaluated on both clinical (growth velocity, height standard deviation scores for chronological age and bone age) and hormonal (urinary growth hormone excretion and insulin-like growth factor I) parameters. Our study shows that long-term clonidine administration in children with short stature did not result in significant differences in growth velocity, height standard deviation scores for chronological age and bone age, insulin-like growth factor I or in urinary growth hormone excretion.

Chronic clonidine treatment and endogenous opioid mechanisms

Chronic clonidine treatment and endogenous opioid mechanisms

Differential effects of clonidine and reserpine treatment on neuropeptide Y content in some sympathetically innervated tissues of the guinea-pig

The effects of treatment with reserpine and/or the selective α 2-adrenoceptor agonists clonidine and oxymetazoline on tissue levels of neuropeptide Y (NPY)-like immunoreactivity (-LI) and noradrenaline (NA) were studied in the guinea-pig. Clonidine treatment was associated with an increase in the levels of NPY-LI in the right atrium in a time- and dose-dependent manner. A significant (45%) elevation of the right atrial content of NPY-LI was present 2 h after administration of clonidine (50 μg kg −1 s.c.). After 24 h of repeated clonidine treatment the atrial levels of NPY-LI had increased by 95%. Following chronic clonidine treatment for two weeks, however, the right atrial NPY levels were similar to those in control animals. The corresponding cell-body content of NPY-LI in the stellate ganglion, remained unaffected by clonidine treatment. The levels of NPY-LI were also increased in the gastrocnemius muscle, spleen and adrenal gland after clonidine treatment while no changes were detected in the vas deferens or hypothalamus. The reserpine-induced reduction of NPY-LI in the right atrium, spleen, gastrocnemius muscle and adrenal gland was markedly inhibited by concomitant clonidine treatment while no effect was observed on NA depletion. The adrenoreceptor antagonists phenotolamine, prazosin and yohimbine all inhibited the increase in cardiac content of NPY-LI seen after clonidine treatment. No elevation of tissue content of NPY-LI was observed after oxymetazoline (50 μg kg −1 s.c.) which, however, reversed the reserpine-induced depletion of NPY-LI. The reserpine-induced increase in content of NPY-LI in the stellate ganglion was also inhibited by clonidine and oxymetazoline. It is concluded that clonidine and oxymetazoline act in opposing directions compared to reserpine on the content of NPY-LI in certain tissues involved in cardiovascular regulation. The mode of action of these α 2-agonists may be related to a centrally reduced sympathetic neuronal activity and an ensuing attenuation of peptide synthesis. Also, an accumulation of peptide in terminal areas due to diminished release via local prejunctional effects could contribute to their effect on NPY levels.

Chronic clonidine treatment produces desensitisation of post but not presynaptic α2-adrenoceptors

Rats were treated chronically with clonidine by osmotic minipump (500 μg/kg daily for 14 days). One day after the end of the infusion period, the animals were pithed, and α 2-presynaptic and -postsynaptic adrenoceptor responses evaluated using inhibition of cardioaccelerator response to sympathetic stimulation by guanabenz, and pressor response to guanabenz respectively. Chronic clonidine treatment had no effect on the presynaptic effect of guanabenz, but the postsynaptic response to this agonist was decreased. In separate group of pithed rats treated chronically with clonidine, there was no alteration in the increment in plasma noradrenalin concentration produced by sympathetic stimulation, and no alteration in the yohimbine-induced enhancement of plasma noradrenaline response to sympathetic stimulation. These data argue against desensitisation of peripheral presynaptic α 2-adrenoceptors by chronic administration of α 2-adrenoceptor agonist. Sympathetic hyperactivity following withdrawal of chronic clonidine treatment may be mediated by down-regulation of postsynaptic α 2-adrenoceptors in the CNS.

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

We have studied the effects of withrawal from chronic clonidine treatment in the adult male spontaneously hypertensive rat (SHR). SHR recieved clonidine, 0.1 mg · kg -1 · day -1 i.v. for 10 days. Clonidine was delivered via osmotic minipumps. After 7 days of treatment there was a 16.5 ± 2.5 mm Hg fall in mean arterial pressure. This was accompanied by a decrease in the dopamine-β-hydroxylase and phenylethanolamine-N-methyl transferase activities of the A1/C1 region. Withdrawal from clonidine was characterized by tachcardia and an increase in mean arterial pressure and heart rate lability. Phenylethanolamine-N-methyl transferase of the A1/C1 region returned to normal but the dopamine-β-hydroxylase activity remained diminished. The dopamine-β-hydroxylase activity of the A2/C2 region was also diminished during withdrawal. We suggest that the blood pressure lowering effect of clonidine is accompanied by a decreased capacity to synthesize adrenaline in the A1/C1 region where adrenaline could mediate a pressor effect. Increased blood pressure lability during withdrawal is accompanied by a restoration of synthesis of adrenaline in the A1/C1 region. There is also a decrease in the capacity of synthesis of noradrenaline in the A2/C2 region where adrenaline may mediate a vasodepressor effect.

P-43 - Alterations in central and renal α-adrenoceptors following chronic clonidine treatment in rats

P-43 - Alterations in central and renal α-adrenoceptors following chronic clonidine treatment in rats

Increase in insulin response to glucose in the rat chronically treated with clonidine.

Effect of chronic clonidine treatment on the response to glucose of rat pancreatic B-cells was investigated. Clonidine treatment was carried out for 10 days by dissolving the drug into drinking water at a concentration of 10 micrograms/ml. Control rats were given drug-free tap water. Serum insulin responses to glucose (750 mg/kg, i.v.) of clonidine-treated rats were much smaller than those of control rats. However, after 1 day's withdrawal of clonidine, the rise in the serum insulin level induced by glucose was approximately 2-fold larger in clonidine-treated rats as compared to that in control rats. Since clonidine treatment decreased body weight of the rat by 10%-20% in 10 days, the same experiments were carried out with rats whose body weight loss was made comparable to that of clonidine-treated rats by restricting food for 10 days. Then, some animals of the group thus treated had food-restriction discontinued for 1 day. In both of the above two groups, no increment in glucose-induced rise in serum insulin level was observed. Islets of Langerhans isolated from clonidine-treated rats showed pronounced insulin releasing capacity in response to glucose. Insulin content per islet of the clonidine-treated rat was slightly larger than that of control rat. These results indicate that the enhancement of serum insulin response to glucose following clonidine treatment is mainly attributable to the hyper-responsiveness developed in the pancreatic B-cells.

Whole blood serotonin and tryptophan levels in Tourette's disorder: Effects of acute and chronic clonidine treatment

Whole blood serotonin (WB5HT) and tryptophan (WBTRP) levels were studied in 20 patients (aged 8 to 45 years) with Tourette's disorder under medication-free baseline conditions and following acute and chronic clonidine treatment. Compared to 87 normal controls, Tourette's disorder patients had lower mean baseline WBTRP levels (mean ± SEM: Tourette's, 5993 ± 304 ng/ml vs. 6822 ± 169 ng/ml; p <.03). No significant differences in mean baseline WB5HT levels were found. Three hours after an acute dose of clonidine (2.5 – 5.1 ug/kg, p.o. at 9:00 A.M.), no mean differences were observed (baseline vs. post 3 hours) in WB5HT or WBTRP levels. However, following chronic treatment (> 3 weeks) with clonidine (3–8 ug/kg/day, p.o.), WB5HT levels were increased in 9 of 14 Tourette's disorder patients. The mean increases in WB5HT levels following chronic clonidine treatment were significant when WB5HT levels were expressed per 10 9 platelets. (mean ± SEM: baseline, 471 ± 45 ng/10 9 platelets vs. chronic, 697 ± 82 ng/10 9 platelets, p = .02). No mean differences in WBTRP levels were observed after chronic clonidine treatment. These findings are discussed in light of a proposed intermediary role of 5HT systems in the mode of action of clonidine in the treatment of Tourette's disorder.

Long-term treatment with clonidine and α-receptors in the brain of Normotensive rats

The aim of the present study was to investigate whether or not changes in rat brain α-adrenoceptors take place during chronic treatment with a low dose of clonidine. Male Wistar normotensive rats were treated with clonidine (0.1 mg/kg) i.p. twice daily for 12 days. This treatment caused a significant increase in [ 3H]clonidine and in [ 3H]WB4101 binding, respectively, to α 2 - and to α 2-adrenoceptors of the frontal cortex; the levels were 30% for [ 3H]clonidine and 20% for [ 3H]WB4101. The Scatchard analysis of data obtained in binding studies indicated that the enhanced binding of two ligands to membranes prepared from chronically clonidine-treated animals, was due to an apparent increase in the number of binding sites. These changes were seen 4 h after administration of the last treatment, before the appearance of the withdrawal syndrome. However, noradrenergic α 2-autoreceptors of synaptosomes, from the frontal cortex and hypothalamus of treated animals, were sensitive to the regulatory action of clonidine or of noradrenaline on the [ 3H]noradrenaline overflow elicited by high K + as well as on the control animals. On the contrary, the α 2-receptors on the serotoninergic nerve terminals from the frontal cortex of treated animals were more sensitive than those of control animals to the action of clonidine or of noradrenaline in counteracting the [ 3H]5-hydroxytryptamine overflow elicited by high K +. These results suggests that during treatment with clonidine no autoreceptor hyposensitivity to the regulatory action of clonidine or noradrenaline on [ 3H]noradrenaline overflow elicited by high K + takes place, but, as a consequence of the diminished noradrenaline availability at the synaptic cleft, the binding of [ 3H]WBA101 to α 1-receptors and of [ 3H]clonidine to pre- and postsynaptic α 2-receptors were significantly elevated in the frontal cortex, a brain areas where the α- 2-receptors are mainly postsynaptic. Thus, the neurotransmitter concentration in the synaptic cleft may be responsible for the trans-synpatic modulation of the α 2-adrenoceptor postsynaptic population. In fact, the α 2-adrenoceptors which are presynaptically located on the serotoninergic terminals, but are postsynaptic in relation to the noradrenergic neurons, also show increased sensitivity after chronic clonidine treatment.

Acute and Chronic CLonidine Treatment in Tourette's Syndrome: A Preliminary Report on Clinical Response and Effect on Plasma and Urinary Catecholamine Metabolites, Growth Hormone, and Blood Pressure

Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of unknown etiology characterized by simple and complex motor and phonic symptoms and behavioral difficulties. Clonidine, an α 2-adrenergic receptor agonist, is useful in the treatment of TS. We report the preliminary results of a series of biological studies undertaken during an open 12-week clinical trial of oral clonidine (2–3 μg/kg/day) in six TS patients. These studies focus on the functional status of central noradrenergic and dopaminergic systems. Specifically, we report the effectgs of a single dose of clonidine (3 μg/kg) p.o., given under double-blind, placebo-controlled conditions, on plasma-free and urinary total 3-methoxy-4-hydroxyphenthyleneglycol (MHPG), plasma homovanillic acid (HVA), plasma human growth hormone (HGH), blood pressure, and sedation under baseline conditions, and after 12 weeks of clonidine therapy. The data do no clearly support the hypothesis that presynaptic noradrenergic receptors are subsensitive in TS or that chronic clonidine treatment increases their sensitivity. However, a significant increase in baseline HVA following chronic clonidine treatment was observed. These preliminary findings are suggestive of a central noradrenergic-dopaminergic interaction in TS. In addition, the clinical response data at 12 weeks, 10–12 months, and following double-blind, placebo-controlled withdrawal of clonidine are presented, and the usefulness of the pretreatment biological measures in predicting the clinical response to clonidine is assessed.

Effect of clonidine on the chronic morphine tolerance and on the sensitivity of the smooth muscles in mice

Clonidine, when administered for prolonged period showed no tolerance to its analgesic activity. Prior exposure to clonidine attenuated the tolerance development to morphine-induced analgesia and the supersensitivity to acetylcholine (ACh) in ileum during chronic morphine treatment. Further, acute administration of lower doses of clonidine (upto 1 mg) produced supersensitivity in ileum to ACh while the higher dose (10 mg) induced subsensitivity. In vas deferens, clonidine in all the concentrations tested induced dose and time dependent supersensitivity to norepinephrine (NE) similar to that produced by morphine. Chronic clonidine treatment failed to alter the ACh responses in ileum while it produced supersensitivity to NE in vas deferens. The results suggest that clonidine and morphine possess comparable properties and the antagonism of chronic morphine tolerance by clonidine may be the therapeutic basis for its clinical application in the treatment of opiate addicts.

An increase in cardiac alpha 1-adrenoceptors following chronic clonidine treatment.

Chronic treatment (22 days) of rats with clonidine (0.5 mg/kg s.c. twice a day followed by 20 h of withdrawal) resulted in a significant increase in the specific [3H]WB4101 binding to ventricular and intraventricular septal alpha 1-adrenoceptors but no alteration of the atrial alpha 1-adrenoceptors. Scatchard analysis indicated that the increase in the [3H]WB4101 binding to the clonidine-treated cardiac tissue was due to an enhancement of the alpha 1-adrenoceptor density since there was a significant increase in the Bmax value for the [3H]WB4101 binding to the treated ventricles without a change in the Kd value. The specific [3H]WB4101 binding to cardiac alpha 1-adrenoceptors was not altered by the acute (1 day) or 7 days treatment with clonidine. Chronic treatment with clonidine had no significant effect on the specific [3H](-)DHA binding to the atrial and ventricular beta-adrenoceptor. The noradrenaline (NA) concentrations in the clonidine-treated ventricles and intraventricular septae were decreased by 16-20%. These data provide biochemical evidence compatible with a significant reduction of sympathetic outflow to the ventricular myocardium by clonidine.

Involvement of central noradrenergic mechanisms in the rebound hypertension following clonidine withdrawal.

The present study was designed to investigate the role of the central nervous system in the rebound hypertension precipitated by abrupt cessation of chronic clonidine (Cl) treatment. Male Wistar rats were treated with Cl (100 micrograms/kg, s.c.) twice daily for 7 days. Systolic blood pressure and heart rate were measured at different time intervals during Cl treatment. Rebound hypertension occurred 16-18 h after the last injection of Cl, but not in control animals given saline (0.1 ml) twice a day for 7 days. Rats were anesthetized with ether during this rebound phase of Cl withdrawal, an electrode inserted into the posterior hypothalamus, and a cannula introduced into the lateral cerebral ventricle. The posterior hypothalamus was electrically stimulated, and voltage-response curves obtained for control and Cl-treated rats revealed that the pressor responsiveness to hypothalamic stimulation was significantly potentiated in the Cl-treated rats. In addition, the depressor response to a single injection of Cl (10 micrograms) into the lateral cerebral ventricle was significantly attenuated in the Cl-treated rats. Additional experiments were performed in pithed rats to determine the involvement of peripheral adrenergic mechanisms in the rebound hypertension. When rats were pithed during the hypertensive phase of withdrawal, the blood pressure of treated rats decreased to a level which was similar to that of control animals. While the pressor responses to total spinal stimulation were similar in both the groups, the effect of exogenous norepinephrine was significantly attenuated in Cl-treated rats., These results suggest that a hyperresponsiveness of central noradrenergic pressor pathways contributes to the rebound hypertension noted following the abrupt cessation of clonidine treatment.