Acute Clonidine Administration Research Articles

Effect of Chronic Clonidine Administration on GH Secretion in Adult Human Subjects

It is well known that the acute administration of clonidine, an alpha 2-adrenergic agonist commonly used as an antihypertensive drug, stimulates GH secretion, likely via hypothalamic growth hormone releasing hormone (GHRH) release. Conversely, evidences of a hyperactivity of GHRH-GH-somatomedin C (SMC) axis during chronical administration of clonidine are controversial. In this study, GH and SMC levels have been evaluated in 16 hypertensive patients chronically treated with clonidine. The subjects were randomized to receive either TRH or saline with the aim of evaluating the non specific GH response to TRH as compared to spontaneous fluctuations during a control test. In basal conditions, GH and SMC concentrations in clonidine treated patients were similar to those observed in an age and sex matched group of normal untreated subjects. An abnormal increase in plasma GH occurred in 5 out of the 10 patients who received TRH, while plasma GH did not show significant variations during testing in the subjects who received saline. It is suggested that chronical administration of clonidine does not induce an hyperactivity of GHRH-GH-SMC axis as estimated by plasma GH and SMC concentrations, but may induce a disorder in hypothalamic control of GH secretion, possibly implicated in the abnormal GH responsivity to TRH.

Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats.

We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 microg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 +/- 3%; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 microg), rilmenidine (7 microg) and LNP 509 (60 microg) were accompanied by significant increases in arteriolar diameter (12 +/- 1, 25 +/- 10 and 21 +/- 4%, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 microg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).

Transiently overexpressed α 2-adrenoceptors and their control of DNA synthesis in the developing brain

During brain development, neurotransmitters act as trophic factors controlling the patterns of cell replication and differentiation. α 2-Adrenoceptors (α 2ARs) are transiently overexpressed in zones with high mitotic activity and we evaluated whether these receptors are linked to DNA synthesis in the perinatal rat brain. Acute administration of clonidine (2 mg/kg), an α 2AR agonist, elicited dramatic decreases in DNA synthesis in the forebrain, brainstem, and cerebellum whether given on gestational day (GD) 21, or on postnatal days (PN) 1 or 8. However, α 2AR blockade elicited by yohimbine (2.5 mg/kg) also resulted in decreased DNA synthesis on GD21 and PN8, albeit to a smaller extent than with clonidine. Yohimbine was able to blunt the effects of clonidine, verifying that both drugs are acting through the same receptor population. Because βARs are also known to regulate DNA synthesis, we used propranolol (10 mg/kg) blockade of βARs to evaluate whether the α 2AR effects were mediated by presynaptic autoreceptors that regulate the release of norepinephrine and consequent βAR responses; the effects of yohimbine were still discernible in the presence of propranolol. Accordingly, transiently overexpressed α 2ARs in the developing brain participate in the control of DNA synthesis in a biphasic manner, with promotional actions at low, endogenous levels of stimulation, but inhibitory effects when stimulation is high. Effects on α 2ARs are likely to contribute to long-term consequences of adrenergic agents used in obstetrics or neurotoxicants that affect adrenergic activity.

Comparative effects of clonidine and dihydroergotamine on venomotor tone and orthostatic tolerance in patients with severe hypoadrenergic orthostatic hypotension

PurposeClonidine, an α2-adrenergic agonist, raises blood pressure in patients with autonomic failure, in whom failure of reflex neurogenic venoconstriction leads to severe orthostatic hypotension. Because animal studies suggest that postjunctional α2-adrenoreceptors are located mainly on venous capacitance rather than arterial resistance vessels, we tested the hypothesis that venoconstriction is the main mechanism by which clonidine raises blood pressure in patients with autonomic failure. Subjects and methodsWe measured forearm venous and arterial tone using plethysmography in 4 patients with autonomic failure before and after acute administration of clonidine (0.4 mg orally) or dihydroergotamine (0.15 mg intravenously), a known venoconstrictor agent. We also recorded supine intraarterial pressure at rest and during graded orthostatic stress with lower body negative pressure. ResultsClonidine and dihydroergotamine caused similar increases in supine (mean ± SD) arterial pressure (+23 ± 11 mm Hg vs. and +27 ± 5 mm Hg) and forearm vascular resistance (+36% ± 13% vs. +28% ± 9%). However, the drugs had different effects on forearm venous tone, which increased by 38% ± 9% with dihydroergotamine (P = 0.01 vs. control) but was unaffected by clonidine (change = 0% ± 14%). A single dose of clonidine was less effective than a single dose of dihydroergotamine in maintaining arterial pressure during graded orthostatic stress. ConclusionIn contrast with what has been hypothesized, clonidine appears to function mainly as an arterial constrictor in patients with hypoadrenergic orthostatic hypotension. Further studies are needed to determine if venoconstrictor agents are of greater therapeutic benefit in this condition than are pure arterial vasoconstrictors.

A Noradrenergic Mechanism Influences the Circadian Timing System in Rats and Hamsters

Brainstem monoaminergic projections to the suprachiasmatic nucleus (SCN), and to the intergeniculate leaflet (IGL), appear to modulate both photic and non-photic effects on the circadian system. Recent work in this laboratory has concentrated on the role of noradrenaline in the regulation of circadian period and phase. Previously, this lab has shown that chronic administration of the alpha2 adrenergic agonist, clonidine, to rats maintained in constant light (LL) shortens free-running circadian period and promotes dissociation of rhythmicity, while acute clonidine administration to hamsters produces phase shifts similar to those observed with photic stimuli. These results suggest an interaction between clonidine and photic input on circadian rhythmicity, and so the present study was designed to examine systematically the relationship between chronic clonidine administration and photic input in both rats and hamsters. In DD and low intensity LL, clonidine did not alter free-running circadian wheel-running rhythms of rats, but under moderate to high intensity LL, clonidine significantly reduced the period-lengthening effects of LL. Chronic clonidine administration also altered several aspects of circadian phase in hamsters; phase shifts in response to light pulses of varying intensity at CT 19 were reduced; steady-state entrainment phase under a 24-h light-dark cycle (LD 14:10)was delayed; and synchronization to a 23-h light-dark cycle (LD 13:10) was impaired. Clonidine appeared to have little effect on free-running period of hamsters, but a trend towards dissociation of rhythmicity under LL was observed. These effects may reflect an action of clonidine at the photic input pathways to the circadian system, or directly at the circadian pacemaker, since alpha 2 adrenoceptors have been localized both in the suprachiasmatic nucleus (SCN) and in several of its projection areas. As both clinical and experimental studies suggest that clonidine may have depressogenic properties, chronic administration of clonidine to rodents may provide an animal model of the alterations in circadian rhythmicity seen in human depression.

Evaluation of the intravenous reinforcing effects of clonidine in baboons

Clonidine HCl is an antihypertensive that is also sometimes used to alleviate symptoms of withdrawal during narcotics detoxification. Recently, there have been reports abuse of clonidine by methadone patients and opioid abusers. The present study evaluated the intravenous self-administration of clonidine in four baboons. Self-injections were available 24 h/day under a fixed-ratio (FR 120 or 160) schedule of injection with a 3-h timeout after each injection. Doses of clonidine (0.0001–0.056 mg/kg per injection) or its vehicle (saline) were substituted for cocaine (0.32 mg/kg) for at least 15 days. Food pellets were available continuously under a concurrent FR 30 schedule of pellet delivery. Clonidine maintained self-injection greater than its saline vehicle in all four baboons. Although self-injection of clonidine increased as a function of dose within each baboon, there were differences between baboons in the range of doses of clonidine that maintained self-injection. Doses of 0.032 or 0.056 mg/kg maintained peak mean levels of clonidine self-injection which ranged from low (3.2 injections/day) to high (>6 injections/day) across baboons. Levels of self-injection were similar to vehicle at 0.01 mg/kg clonidine in two of four baboons. However, in the other two baboons, very low doses of clonidine (0.0001–0.001 mg/kg) maintained low to moderate levels of self-injection. Acute administration of clonidine produced signs of sedation including lip droop, drooling and sitting with eyes closed. At high doses, some toxicity was apparent: Baboons were pale and not responsive. Food intake was generally increased in a dose dependent manner. The present study indicates that clonidine functions as a positive reinforcer.

Effects of acute clonidine administration on power spectral analysis of heart rate variability in healthy humans.

1. To investigate the relationship between the autonomic drive to the heart and heart rate variability, as evaluated by power spectral analysis, we studied the effect of clonidine (300 microg), a central sympatholytic agent, on heart rate variability. 2. Six healthy subjects (mean age 31 +/- 3 years) were studied in the supine and the sitting position (15 min each) on two different occasions, respectively, before and after clonidine administration. Using an autoregressive approach, the low frequency (LF) and the high frequency (HF) components of power spectral analysis were measured, and their ratio was calculated. Blood pressure was monitored throughout the study and plasma catecholamines were measured at the end of each period. 3. Before clonidine, assumption of the sitting position induced increases in LF, LF/HF ratio, blood pressure and plasma noradrenaline. Clonidine induced remarkable reductions in the normalized values of the LF component and the LF/HF ratio in both the resting and the sitting position (supine: LF = -68%, LF/HF ratio = -80%; sitting: LF = -23%, LF/HF ratio = -55%) without affecting the central frequencies of LF and HF components. Blood pressure and plasma catecholamines also significantly decreased after clonidine. 4. These results support the hypothesis that the LF component of HRV, expressed in normalized units, is an indicator of the sympathetic control of the heart. In addition, this component seems to be largely of central origin, because it is markedly reduced by the central sympatholytic action of clonidine.

Antagonist precipitated clonidine withdrawal in rat: Effects on locus coeruleus neurons, sympathetic nerves and cardiovascular parameters

The goal of the present study was to examine the effect of clonidine withdrawal on the neural control of blood pressure. Rats were treated for 7–13 days with clonidine via osmotic minipumps (200 μg kg −1 day −1, s.c.). Controls received saline or were sham operated. Withdrawal was precipitated by the α 2-adrenergic receptor ( α 2-AR) antagonist atipamezole. Most experiments were done under halothane anesthesia. Chronic treatment with clonidine did not change mean arterial pressure (MAP) or heart rate (HR) but raised femoral artery resistance and the activity of locus coeruleus neurons slightly. Atipamezole given to rats treated chronically with clonidine produced the following effects: no change in MAP, severe tachycardia, sustained increase in splanchnic sympathetic nerve discharge (SND; +75±13%), transient increase in lumbar SND (+23±7%), ON–OFF activity pattern in the locus coeruleus (LC). The ON phase of LC activity was synchronized with upswings of SND and with small changes in MAP. A second α 2-AR antagonist, methoxyidazoxan, produced effects identical to those of atipamezole. Atipamezole given to control rats produced no effect on MAP, HR, SND or LC activity. Atipamezole reversed the hypotension, sympathoinhibition and bradycardia produced by acute administration of clonidine. In awake rats treated chronically with clonidine, atipamezole did not change MAP but produced arterial pressure lability and tachycardia. In conclusion, under anesthesia, selective α 2-AR antagonists elicit a clonidine withdrawal syndrome that displays autonomic characteristics reminiscent of the spontaneous withdrawal syndrome found in awake rats. The most prominent features of this syndrome are tachycardia, sympathoactivation, lack of hypertension and an oscillating activity pattern of brainstem neurons leading to abrupt changes in SND and in MAP.

Noradrenergic receptor sensitivity in obsessive compulsive disorder: II. Cortisol response to acute clonidine administration

Sensitivity of pre-synaptic α-2- and post-synaptic α-1- and β-adrenoceptors was investigated in 15 patients with obsessive-compulsive disorder (OCD) and in 15 age- and sex-matched healthy controls, by measuring cortisol responses to saline administration and to inhibition by clonidine (clon), a noradrenergic receptor agonist. Basal values of cortisol and responses to administration of saline and of clon were the same in patients and controls.

Noradrenergic and dopaminergic interrelation in schizophrenia

Growth hormone (GH) and prolactin (PRL) responses to the acute administration of clonidine (150 μg) and apomorphine (0.5 mg) were investigated in parallel in 20 drug-free subchronic and chronic sghizophrenic patients and in nine control subjects. Neither basal levels of the two hormones nor their mean responses to both stimuli differed significantly between the two groups. However, eight patients had blunted GH responses to clonidine and seven to apomorphine; only two patients showed blunted GH responses to both stimuli. The blunted GH response to apomorphine correlated with the chronicity of the disorder. A greater than normal GH response to clonidine stimulation was observed in paranoid patients. Significant correlations were observed between negative symptoms and GH responses to clonidine (negative), between negative symptoms and PRL responses to apomorphine (positive), and between positive symptoms and PRL responses to apomorphine (negative).

Long-term sympathetic and hemodynamic responses to clonidine in patients with cirrhosis and ascites

The aim of the present study was to examine the short- and long-term effects of the alpha 2-agonist clonidine on sympathetic overactivity, systemic, splanchnic, and renal circulation changes, and abnormal renal sodium excretion in cirrhotic patients with ascites. Of 17 patients, 8 received clonidine and 9 a placebo. Measurements were taken before and after either a single dose of clonidine (150 micrograms) and placebo or a 1-week treatment with clonidine (150 micrograms/day) and placebo. Clonidine but not placebo induced significant short- and long-term decreases in plasma norepinephrine concentrations in the pulmonary artery and the right renal vein. Acute clonidine administration induced a significant reduction in cardiac output, heart rate, arterial pressure, and hepatic venous pressure gradient but had no effect on renal hemodynamics. Long-term clonidine administration induced a significant decrease in the hepatic venous pressure gradient from 20.1 +/- 1.9 to 17.6 +/- 2.0 mm Hg (mean +/- SEM) but had no significant effects on systemic or renal hemodynamics or renal excretion of sodium. It is concluded that long-term clonidine administration in cirrhotic patients induced a sustained decrease in sympathetic nervous activity and portal pressure. In contrast, clonidine had no prolonged effect on systemic hemodynamics. In addition, short- and long-term clonidine administration did not modify renal hemodynamics or induce a natriuretic response in patients with ascites. (Gastroenterology 1992 Apr;102(4 Pt 1):1309-18)

Long-term sympathetic and hemodynamic responses to clonidine in patients with cirrhosis and ascites

The aim of the present study was to examine the short- and long-term effects of the α2-agonist clonidine on sympathetic overactivity, systemic, splanchnic, and renal circulation changes, and abnormal renal sodium excretion in cirrhotic patients with ascites. Of 17 patients, 8 received clonidine and 9 a placebo. Measurements were taken before and after either a single dose of clonidine (150 μg) and placebo or a 1-week treatment with clonidine (150 μg/day) and placebo. Clonidine but not placebo induced significant short- and long-term decreases in plasma norepinephrine concentrations in the pulmonary artery and the right renal vein. Acute clonidine administration induced a significant reduction in cardiac output, heart rate, arterial pressure, and hepatic venous pressure gradient but had no effect on renal hemodynamics. Long-term clonidine administration induced a significant decrease in the hepatic venous pressure gradient from 20.1 ±1.9 to 17.6 ± 2.0 mm Hg (mean ± SEM) but had no significant effects on systemic or renal hemodynamics or renal excretion of sodium. It is concluded that long-term clonidine administration in cirrhotic patients induced a sustained decrease in sympathetic nervous activity and portal pressure. In contrast, clonidine had no prolonged effect on systemic hemodynamics. In addition, short- and longterm clonidine administration did not modify renal hemodynamics or induce a natriuretic response in patients with ascites.

Functional Interrelationships Between Adrenergic and Opioid Systems in the Neuroregulation of Growth Hormone Secretion in Infant Rats

Abstract Functional interrelationships between hypothalamic adrenergic and opioid systems were studied in 10-day-old male and female rats. Either clonidine (150 mug/kg, sc), an alpha(2)-adrenoceptor agonist, or FK 33-824 (1 mg/kg, sc), a synthetic analog of met-enkephalin, increased plasma growth hormone (GH) levels, the increment being significantly higher with FK 33-824 than with clonidine. Pharmacologic blockade of opioid receptors with naloxone (5 mg/kg, sc) did not modify either basal GH levels, or the GH response to clonidine, whereas blockade of alpha(2)-adrenoceptors with yohimbine (2.5 mg/kg, sc) reduced basal GH levels and partially counteracted the FK 33-824-induced GH rise. Clonidine (150mu/kg, sc, twice daily) administered from postnatal day 5 to 9, increased basal GH levels and pituitary GH content. In these pups, acute administration of clonidine failed to further release GH, but the GH response to acute administration of FK 33-824 was significantly enhanced. A 5-day treatment with FK 33-824 (1 mg/kg, sc, twice daily), neither modified basal GH levels, nor pituitary GH content. Under these conditions, the in vivo GH response to an FK 33-824 challenge was significantly enhanced, and the response to clonidine was preserved. Pituitaries from FK 33-824-pretreated rats were hyperresponsive to GH-releasing hormone (10(-7) M). In summary, our data indicate that in rat pups: 1) two separate components i.e. one adrenergic, the other extra-adrenergic, subserve the GH-releasing effect of opioid peptides; 2) in contrast to short-term stimulation of alpha(2)-adrenoceptors, stimulation of opioid receptors does not trigger GH synthesis or induce down-regulation or tolerance; 3) short-term opioid stimulation does not affect an alpha(2)-adrenergic challenge, but sensitizes to an opioid challenge.

Acute Clonidine Administration Potentiates Spontaneous Diurnal, but not Nocturnal, Growth Hormone Secretion in Normal Short Children

It has been shown that alpha 2-adrenoreceptor activation induced by clonidine (CLON) increases plasma GH levels in both adults and children. In this study the effects of CLON (150 micrograms/m2, orally) on GH secretion were studied both in the morning (from 0800-1100 h) and at night (from 2300-0200 h) in nine short children previously shown to have normal spontaneous nocturnal GH secretion. In the morning, CLON induced a GH increase higher than placebo [peak (mean +/- SEM), 23.8 +/- 4.3 vs. 3.4 +/- 1.4 micrograms/L; P = 0.0001; area under curve (AUC), 624.4 +/- 62.7 vs. 135.6 +/- 33.3 micrograms/L.h; P less than 0.00001]. In the night, no difference was observed between GH secretion after CLON (peak, 15.4 +/- 3.2 micrograms/L; AUC, 562.2 +/- 57.5 micrograms/L.h) and placebo (peak, 13.1 +/- 4.7 micrograms/L; AUC, 497.2 +/- 83.5 micrograms/L.h). Spontaneous GH secretion was higher during the night than in the morning (P = 0.0001), whereas nocturnal GH secretion overlapped with that in the morning after CLON. The data presented show that alpha 2-adrenoreceptor activation is probably mediated by increased endogenous GHRH release; our results suggest that the endogenous GHRH secretion is maximally stimulated at night.

Hypothalamic Neurochemistry and Feeding Behavioral Responses to Clonidine, an Alpha-2-Agonist, and to Trifluoromethylphenylpiperazine, a Putative 5-Hydroxytryptamine-1B Agonist, in Genetically Obese Zucker Rats

Genetically obese Zucker rats are hyperphagic, hyperinsulinemic and hyperlipemic. In order to investigate pathophysiological mechanisms underlying hyperphagia in these animals, monoamine metabolism and turnover were studied in discrete hypothalamic nuclei known to participate in the control of feeding behavior. Neurochemical studies in genetically obese Zucker rats and in their lean littermate controls were complemented by investigating feeding behavioral responses to the acute administration of clonidine (15 and 30 micrograms/kg i.p.), an alpha 2-adrenoceptor agonist, and to trifluoromethylphenylpiperazine (TFMPP; 1, 2 and 5 mg/kg s.c.), a putative serotonergic 5-hydroxytryptamine-1B receptor agonist. Obese Zucker rats had significantly lower concentrations of 5-hydroxyindoleacetic acid, the main deaminated metabolite of 5-hydroxytryptamine, in the nucleus paraventricularis (PVN) and in the nucleus ventromedialis (VMN), when compared to their lean littermate controls. The rate of accumulation of 5-hydroxytryptophan after decarboxylase inhibition was reduced in the PVN, nucleus supraopticus, nucleus periventricularis and nucleus suprachiasmaticus of the obese rats. No differences were observed in basal concentrations of norepinephrine, dopamine or 3,4-dihydroxyphenylacetic acid between obese and lean Zucker rats in the brain areas studied. However, the rate of accumulation of 3,4-dihydroxyphenylalanine was lower in the VMN and in the median eminence of the obese rats. The feeding behavioral tests showed significantly augmented hyperphagic responses to clonidine in obese Zucker rats. The anorexic effect of TFMPP was similar in both phenotypes. It is concluded that serotonergic activity is reduced in obese Zucker rats, particularly in the PVN, which plays a key role in the control of feeding behavior. The reduced serotonergic activity may be associated with enhanced alpha 2-adrenoceptor-mediated feeding responses in obese Zucker rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Galanin on Growth Hormone Secretion in Children of Normal and Short Stature1

We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 micrograms/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 micrograms/kg/h of Gal infusion (13.3 +/- 1.7 ng/mL; mean +/- SEM) was higher (p less than 0.02) than in NS children (8.5 +/- 0.8 ng/mL). When the dose of Gal was increased to 15 micrograms/kg/h the mean plasma GH peak in CGD children (18.5 +/- 3.5 ng/mL) was still higher than in the NS group (13.2 +/- 2.9 ng/mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 micrograms/kg/h of Gal (3.8 +/- 0.7 and 3.9 +/- 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p less than 0.0002) or NS children (p less than 0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 +/- 3.0 ng/mL) was higher than that observed after either dose of Gal used (p less than 0.001 and p less than 0.05 with 8 and 15 micrograms/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 +/- 2.6 and 4.1 +/- 1.2 ng/mL, respectively) was not significantly different from that observed after either dose of Gal.(ABSTRACT TRUNCATED AT 250 WORDS)

α-Adrenoceptor Influence on Plasma Levels of Neuropeptide Y-Like Immunoreactivity and Catecholamines During Rest and Sympathoadrenal Activation in Humans

Antecubital venous plasma neuropeptide Y-like immunoreactivity (NPY-LI) and catecholamines were analyzed in six healthy volunteers performing a graded bicycle exercise without medication and after acute administration of clonidine, phentolamine, and nifedipine. During the control exercise, plasma noradrenaline (NA), adrenaline (A), and NPY-LI increased to 17-, 7-, and 3-fold the resting values, respectively, at a maximal workload. Clonidine (300 micrograms p.o.) reduced resting and exercising heart rate (HR) and systolic blood pressure (SBP). Plasma NA at rest decreased and NA, A, and NPY-LI were 40-60% lower during the exercise after clonidine compared to the control. Phentolamine (0.07 mg X kg-1 every 10 min i.v.) and nifedipine (20 mg p.o.) increased HR and reduced SBP during the exercise. Plasma NA at rest was elevated threefold and the exercise-induced increases in NA and A were also enhanced after phentolamine. Plasma NPY-LI at rest was unchanged by phentolamine, while it was increased five-fold, as compared to the control, at the highest workload. Nifedipine slightly enhanced plasma NA and NPY-LI but not A during exercise. It is suggested that NPY is released mainly at high levels of sympathetic activity and that blood-pressure-lowering drugs acting on alpha adrenoceptors acutely influence the release of both NA and NPY-LI from sympathetic nerves in humans.

Clonidine effects on disposition of xenobiotics in rats: inhibited elimination of flow-limited but not extraction-limited agents.

1. The alpha 2-adrenoceptor agonist, clonidine, reduces the hepatobiliary clearance of the anionic dye, sulphobromophthalein (BSP) in rodents. We now compare the effects of clonidine on BSP elimination with its effects on disposition of compounds which are metabolized by hepatic microsomal mixed function oxidases. 2. BSP, 100 mg kg-1 was administered i.v. to rats at 4 h after s.c. saline or clonidine, 0.2 mg kg-1. Thirty min later, plasma BSP levels were 121.4 +/- 2.25 micrograms ml-1 in saline-treated rats, while in clonidine-treated rats they were 631.5 +/- 141.0 micrograms ml-1. Clonidine raised hepatic BSP levels from 256.0 +/- 28.9 micrograms g-1 tissue to 568.5 +/- 86.5 micrograms g-1. 3. Acute administration of clonidine (0.2 mg kg-1 s.c.) or repeated clonidine dosing (0.2 mg kg-1, s.c. twice daily for 10 days) did not affect the disposition of intravenously administered [14C]-antipyrine (15 mg kg-1). 4. Activities of the P450 mixed function oxidase enzymes, aniline hydroxylase and aminopyrine N-demethylase, were identical in liver microsomes from saline-treated rats and in microsomes from rats given single or multiple s.c. doses of clonidine (0.2 mg kg-1). 5. Addition of clonidine or other 2-substituted imidazoles at concentrations up to 2 microM did not affect the activities of aniline hydroxylase or of aminopyrine N-demethylase in suspensions of rat liver microsomes. Other substituted imidazoles, including cimetidine, clotrimazole and metronidazole, at concentrations of 0.2 microM or higher, inhibited the activities of these microsomal enzymes. 6. Clonidine slowed BSP elimination, which is probably hepatic blood flow-limited, but not the extraction-limited elimination of antipyrine, which is metabolized by hepatic microsomal enzymes.

Behavioural and neuropharmacological properties of the dibenzazepines, desipramine and lofepramine: studies on the olfactory bulbectomized rat model of depression

O'Connor, William T. and Brian E. Leonard: Behavioural and Neuropharmacological Properties of the Dibenzazepines, Desipramine and Lofepramine: Studies on the Olfactory Bulbectomized Rat Model of Depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12 : 41–51. 1. 1. Lofepramine was compared with its major desipramine for its effects on adaptation to novel objects in the home cage (neophobia) and exploratory behaviours in both sham operated and olfactory bulbectomized rats. 2. 2. In the test for neophobia (marble burying), the aversive response of bulbecotmized rats differed from that of the sham operated animals, the bulbectomized rats showing a diminished aversive response. This response was unaffected by either antidepressant. 3. 3. Of two tests for exploratory activity, the “open field” test clearly differentiated the bulbectomized rats treated with desipramine from those treated with lofepramine. In the lower doses used (1 and 10 mg/kg), only desipramine treatment significantly attenuated the hypermotility of the bulbectomized rats. In high doses (30 mg/kg), lofepramine also attenuated the hypermotility of the bulbectomized rats; this could have been due to the presence of high concentrations of the desipramine metabolite. In a nonstressful novel environment (‘hole board’), neither drug significantly affected the behaviour of sham operated or olfactory bulbectomized rats. Neither antidepressant had noticeable anticholinergic properties as indicated by the number of faecal boli deposited. 4. 4. Acute clonidine administration was found to attenuate the activity of rats in the ‘open field’ apparatus. This effect was attenuated following the chronic administration of desipramine but not lofepramine. It may be concluded that the pharmacological activity of lofepramine is independent of its metabolism to desipramine in vivo .

The sympathetic nervous system in essential hypertension

Enhanced activity of the sympathetic nervous system (SNS) could contribute to essential hypertension (EH). Resuts of over 80 studies measuring norepinephrine (NE) in EH patients show that only a minority of younger EH patients have elevated plasma NE. Younger EH patients also have increased renal NE spillover and elevated 24-hour NE levels. Another method to evaluate SNS in EH patients is examination of depressor responses to SNS blocking agents. The level of plasma NE predicts the degree of depressor response after acute clonidine administration in EH patients, suggesting increased SNS outflow in EH. Stimulation of SNS activity by stress, isometric exercise, or tilt table shows exaggerated NE responses in EH patients and young normotensive individuals from hyprtensive-prone families. EH patients with high plasma NE tend to be younger, thinner, have higher pulse rates, greater cardiac indices, accentuated depressor responses to SNS inhibition, and blunted baroreflex sensitivity. Patients with EH also display enhanced vascular reactivity to infused NE despite high plasma NE, which should normally blunt vascular reactivity. Baroreceptors modulate blood pressure increases through central inhibition of SNS outflow. EH patients display diminished baroreceptor control early in the development of EH, as seen in younger patients with borderline or mild EH. However, most evidence indicates that baroreflex abnormalities in EH are a secondary event. Elevations of plasma epinephrine (E) are also seen in EH. Stress in EH subjects causes increases in plasma E, accompanied by sodium retention and enhanced vascular reactivity. Stress-induced increases in plasma E may result in prejunctional uptake of E in nerve terminals with release of E as a cotransmitter with NE—i.e., facilitation of NE release leading to postjunctional vasoconstriction and hypertension. Another catecholamine product of SNS activity, dopamine (DA), may contribute to EH by its effects on aldosterone and sodium excretion. DA inhibits aldosterone secretion and enhances sodium excretion. Studies in EH patients show reduced urinary-free DA responses to salt loading. This suggests an intrinsic deficiency of DA-modulated natriuretic mechanisms in EH.