Intravenous Administration Of Clonidine Research Articles

Comparison of Effect of Clonidine and Magnesium Sulphate on Attenuation of Haemodynamic Response to CO2 Pneumoperitoneum in Patients Undergoing Laparoscopic SurgeriesA Randomised Clinical Study

Introduction: Laparoscopy, a minimally invasive technique causes several physiological fluctuations. There can be deleterious sympathetic responses during carbon dioxide insufflation, which is done to create a pneumoperitoneum. Aim: To assess the impact of clonidine and magnesium sulphate on sympathetic response to carbon dioxide insufflation in patients undergoing laparoscopic surgeries. Materials and Methods: A double-blinded randomised clinical study was conducted in Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune, Maharshtra, India, from June 2020 to September 2021, included 52 patients, posted for elective laparoscopic surgeries. Patients were randomized into two groups i.e, group M (n=26) received 30 mg/kg of magnesium sulphate and group C (n=26) received 1 μg/kg of clonidine after premedication. The vital parameters like heart rate, systolic, diastolic and mean arterial pressure, end tidal carbon dioxide, saturation were observed and noted at predetermined interval in perioperative period. Also, Visual Analogue Score (VAS) and sedation score were recorded in the recovery room. The statistical software SPSS version 16 was used. The p-value <0.05 was considered as significant. Results: The mean age in group C and group M was 35.46± 8.5 years and 35.38±9.02 years (p-value=0.751). Both groups were compared for change in heart rate, systolic, diastolic and mean blood pressure changes after pneumoperitoneum and showed no significant variations in both groups at different time intervals (p-value >0.05). Also, both groups showed less than 20% variation from the baseline parameters, thus, effectively attenuating the pressor response. The VAS and sedation score were comparable in both the groups and showed no significant variations in both groups at different time intervals. Conclusion: Intravenous administration of clonidine 1 μg/kg, or magnesium sulfate 30 mg/kg prior to pneumoperitoneum was effective in suppressing the pressor response during laparoscopic procedures. At the above used dosages, groups C and M showed insignificant difference in the measured parameters, thus proving to be equally effective in blunting the pressor response.

Aortic stiffness is sympathetically mediated in fructose‐induced salt‐sensitive hypertension

Introduction Hypertension is one of the leading risk factors for major adverse cardiovascular events (MACE). Likewise, suboptimal dietary habits, including high fructose and sodium intake, are major leading causes of mortality. High dietary fructose alone predisposes to salt-sensitivity of blood pressure, which is an independent, significant cardiovascular risk factor. Aortic stiffness is now recognized as the most robust predictor of MACE and renal failure. Sympathoexcitation also imparts increased cardiovascular risk. Emerging data show that sympathetic inputs strongly impact aortic stiffness, and renal sympathetic denervation improves aortic distensibility. Recently published studies from our laboratory showed that with even short-term fructose in combination with high salt intake renal sympathetic nerve activity (RSNA) is significantly elevated prior to any increase in blood pressure and is responsible for activation of the renin-angiotensin-aldosterone system (RAS). Most recently, we also reported increased aortic stiffness in the fructose-induced salt-sensitive hypertension rat model. The present investigation was designed to assess the impact of acute blockade of RAS and/or sympathetic nervous activity on cardiovascular function in a rat model of fructose- induced salt-sensitive hypertension. Methods Sprague-Dawley rats were placed on a diet containing either 20% fructose or 20% glucose in their drinking water while consuming normal sodium. After one week, the fructose group was switched to a 4% sodium chow (FHS) and the rats were maintained on their respective diets for two additional weeks. At the beginning of week three, arterial and venous catheters were implanted and rats allowed to recover for one day. The following day, aortic pulsed wave velocity was measured using Vevo3100 ultrasound at two time points: 1) at baseline and 2) after intravenous injection of either sympatholytic agent clonidine, RAS inhibitor enalapril or diuretic hydrochlorothiazide (HCTZ). Blood pressure and heart rate were monitored throughout the entire experiment. Results Intravenous administration of clonidine, a central sympatholytic agent, reduced MAP and PWV in FHS rats significantly (by 23 ± 3 mmHg and by 212 ± 39 mm/s, respectively). A similar decline in blood pressure occurred in control rats (27 mmHg) but PWV did not change. The dose of enalapril used to inhibit RAS was chosen to provide a similar decline in MAP as clonidine. The reduction in MAP was slightly less profound (17 ± 4 mmHg); nonetheless, only a minimal change was observed in PWV in FHS (10 ± 6 mm/s) and no change in control rats. The diuretic HCTZ given acutely did not change either MAP or PWV. Conclusion Increase in aortic stiffness after two weeks of fructose and high salt diet appears to be sympathetically driven, since the abrogation of the sympathetic activity with clonidine decreased PWV in FHS rats. The effects of the RAS blockade may require a longer period of treatment to permit vascular remodeling and other cellular mechanisms and, thus, may not have been observable in an acute setting. Likewise, the intravascular volume changes due to the diuretic may also require longer exposure.

Influence of Clonidine on Antihypertensive Selective Afferent Vagal Nerve Stimulation in Rats

Selective-afferent vagal nerve stimulation (sVNS) may be a treatment option for therapy-resistant hypertension, as it lowers blood pressure (BP) in rats without causing significant side effects. Alpha-2-agonists are widely used for the treatment of withdrawal, chronic pain and other disorders, and even if sVNS becomes a treatment option for therapy resistant hypertension, in some patients it might be necessary to combine sVNS with an alpha-2-agonist like clonidine. Alpha-2-agonists exhibit a central and peripheral mechanism of action. This study investigated the influence of the commonly used alpha-2-agonist clonidine on sVNS. A polyimide multichannel-cuff-electrode was placed around the left vagal nerve bundle including the aortic depressor nerve (ADN) in eight male Wistar rats for the focused stimulation of baroreceptive fibers of the ADN. Stimulation parameters were adapted to the thresholds of the individual animals and ranged from frequencies between 30 and 50 Hz, amplitudes of 0.5-0.9 mA and pulse widths between 0.4 and 0.8 ms. BP was recorded using a microtip transducer in the left carotid artery, and electrocardiography was registered using subcutaneous needle electrodes. Before clonidine, we found a frequency-dependent drop of BP with maximum at 40 Hz. The animals' mean arterial blood pressures and respiration rate dropped after intravenous clonidine administration (10 µg/kg bodyweight), and sVNS still decreased in BP, but they did so to a lesser extent. Unwanted bradycardia, which was expected by the superimposition of sVNS and clonidine, did not occur. Left-sided vagotomy abolished the respiratory depressant effect of clonidine and blunted the BP reducing effect of sVNS while sVNS hardly affected heart rate anymore. The effect of sVNS on BP is dampened by clonidine, but sVNS can still lower the BP in clonidine treated rats without causing significant bradycardia.

Effect of Endothelin-1 on Baroreflexes and the Cardiovascular Action of Clonidine in Conscious Rabbits.

We studied the influence of pretreatment with endothelin–1 on cardiac baroreflexes and on the effect of clonidine on blood pressure and heart rate. In order to avoid the complication of the direct vasoconstrictor effects of endothelin-1, initial dose-response studies in animals treated with a ganglion blocker were performed. Intravenous administration of 50, 200, and 1200 ng/kg of endothelin-1 produced biphasic changes in blood pressure, consisting of an immediate depressor response, followed by a long lasting and dose-dependent pressor effect (peak response 3 ± 1, 9 ± 3, and 33 ± 5 mmHg, respectively). Thus, the 50 ng/kg dose of endothelin-1 was used in subsequent studies. Conscious rabbits were pretreated on separate days with endothelin-1, either intravenously (50 ng/kg) or intracisternally (10 and 50 ng/kg), or with vehicle. The animals then received an intravenous dose (20 μg/kg) or an intracisternal dose (1 μg/kg) of clonidine and the effects on blood pressure and heart rate were measured. In vehicle-treated rabbits, the intravenous administration of clonidine induced a significant decrease in blood pressure and heart rate (15 min after injection: −15.7 ± 4.7 mmHg and −33 ± 4 b/min, respectively). Similarly, the intracisternal injection of clonidine lowered blood pressure (−16.0 ± 2.5 mmHg), but produced a less pronounced bradycardia (−18 ± 4 b/min). Endothelin pretreatment, either 50 ng/kg centrally or peripherally, had no significant effect on the hypotension or bradycardia produced either by central or peripheral injection of clonidine. At this dose, endothelin by itself did not produce significant changes in blood pressure or heart rate. There was a reduction of the gain of the baroreceptor-heart rate reflex with intracisternal endothelin-1. These results suggest that central 2–adrenoceptor mechanisms involved in clonidine-induced hypotension and bradycardia do not appear to be influenced by activation of endothelin receptors.

Effects of intravenous clonidine on haemodynamics and on plasma cortisol level during laparoscopic cholecystectomies.

Both mechanical and neurohumoral factors contribute to the haemodynamic changes induced by carbon dioxide pneumoperitonium (PNP). Several mediators have been proposed.[1] Clonidine is a α-2 adrenoreceptor agonist and has been shown to reduce perioperative haemodynamic instability during laparoscopic surgeries. Other investigators have suggested a possible effect of clonidine in controlling excessive stress responses during surgical procedures.[2,3] In the present study, the effects of intravenous administration of clonidine on sympathetic and hormonal responses were investigated in patients undergoing elective laparoscopic cholecystectomy. The aim of this study was to investigate the effects of intravenously (IV) administered 3 μg/kg clonidine as pre-anaesthetic medication on haemodynamics and plasma cortisol levels which is one of the markers of the stress response.

Intravenous clonidine administration and its ability to reduce pulmonary arterial pressure in patients undergoing heart surgery

ObjectiveEvaluate the ability of clonidine to reduce pulmonary arterial pressure in patients with pulmonary hypertension undergoing heart surgery, either by reducing the pressure values from the direct measurement of pulmonary arterial pressure or by reducing or eliminating the need for intraoperative dobutamine and nitroprusside. MethodRandomized, double-blind, placebo-controlled, comparative study conducted in 30 patients with pulmonary arterial hypertension type 2 undergoing cardiac surgery. Mean pulmonary arterial pressure and dosage of dobutamine and sodium nitroprusside were assessed four times: before intravenous administration of clonidine (2μg/kg) or placebo (T0), 30min after tested treatment and before cardiopulmonary bypass (T1), immediately after CPB (T2), 10min after protamine injection (T3). ResultsThere were no significant differences regarding mean pulmonary arterial pressure at any time of evaluation. There was no significant difference between groups regarding other variables, such as mean systemic arterial pressure, heart rate, total dose of dobutamine, total dose of sodium nitroprusside, and need for fentanyl. ConclusionData analysis from patients included in this study allows us to conclude that intravenous clonidine (2μg/kg) was not able to reduce the mean pulmonary arterial pressure in patients with pulmonary hypertension in group 2 (pulmonary venous hypertension), undergoing heart surgery, or reduce or eliminate the need for intraoperative administration of dobutamine and sodium nitroprusside.

Suppression of the cough reflex byα2-adrenergic receptor agonists in the rabbit

The α2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans. We investigated the effects of the α2-adrenergic receptor agonists, clonidine and tizanidine, on cough responses induced by mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30–50 nL) into the caudal nucleus tractus solitarii (cNTS) and the caudal ventral respiratory group (cVRG) as well as administered intravenously in pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bilateral microinjections of clonidine into the cNTS or the cVRG reduced cough responses at 0.5 mmol/L and abolished the cough reflex at 5 mmol/L. Bilateral microinjections of 0.5 mmol/L tizanidine into the cNTS completely suppressed cough responses, whereas bilateral microinjections of 5 mmol/L into the cVRG only caused mild reductions in them. Depressant effects on the cough reflex of clonidine and tizanidine were completely reverted by microinjections of 10 mmol/L yohimbine. Intravenous administration of clonidine (80–120 μg/kg) or tizanidine (150–300 μg/kg) strongly reduced or completely suppressed cough responses. These effects were reverted by intravenous administration of yohimbine (300 μg/kg). The results demonstrate that activation of α2-adrenergic receptors in the rabbit exerts potent inhibitory effects on the central mechanism generating the cough motor pattern with a clear action at the level of the cNTS and the cVRG.

Endothelin modulates the cardiovascular effects of clonidine in the rat

Clonidine decreases mean arterial pressure (MAP) by acting as an α 2-adrenergic receptor (AR) agonist in the central nervous system; it also acts on peripheral α-ARs to produce vasoconstriction. Endothelin (ET) has been shown to modulate the action of ARs. The present study was conducted to determine the involvement of ET in cardiovascular effects of clonidine. Intravenous administration of clonidine (10, 30 and 90 μg kg −1) produced a dose-dependent decrease in MAP and heart rate (HR). Treatment with ET-1 (100, 300 and 900 ng kg −1) significantly attenuated clonidine (10 μg kg −1) induced fall in MAP and HR. Rats treated with ET-1 (900 ng kg −1) showed an increase in MAP and HR after clonidine administration compared to untreated rats, while ET A/B antagonist, TAK-044 (1 mg kg −1) and ET A antagonist, BMS-182874 (9 mg kg −1) potentiated the hypotensive effect of clonidine. ET B receptor agonist, IRL-1620 (5 μg kg −1) produced significant attenuation of clonidine induced fall in MAP and HR, while ET B receptor antagonist, BQ-788 (0.3 mg kg −1), potentiated the hypotensive effect of clonidine. Prazosin (0.1 mg kg −1) completely blocked ET-1 induced changes in cardiovascular effects of clonidine. Clonidine-induced contraction of rat abdominal aortic ring was potentiated by ET-1, which was completely blocked by prazosin. Clonidine produced an increase in ET A receptor expression in the brain and abdominal aorta while ET B receptors were not affected. It is concluded that ET enhances the responsiveness of vascular ARs to the constrictor effect of clonidine and ET antagonists potentiate the hypotensive effect of clonidine suggesting that a combination of ET antagonist with clonidine may be a useful option to treat hypertension.

Intravenous administration of clonidine reduces intraocular pressure and alters ocular blood flow

Aim:To evaluate the effect of intravenously administered clonidine on ocular blood flow in healthy volunteers.Methods:A randomised, double-masked, placebo-controlled, two-way crossover study was performed in 12 healthy young volunteers. Clonidine (0.2...

Increased Postoperative Arterial Blood Pressure Stability with Continuous Epidural Infusion of Clonidine in Children

To the Editor: We want to add additional information to our previous study published in Anesthesia & Analgesia(1). This information concerns the variability of postoperative hemodynamic variables associated with continuous postoperative epidural infusion of clonidine and ropivacaine in children. Following Ethical Committee approval and written parental informed consent, 60 boys (ASA physical status 1–2) aged 1–4 yr undergoing hypospadias repair were randomized to receive one of the following four postoperative epidural infusions after the induction of a standardized isoflurane based anesthetic: Group R: plain ropivacaine 0.1%, 0.2 mg kg−1h−1; Group RC1: ropivacaine 0.08% 0.16 mg kg−1 h−1 + clonidine 0.04 μg −1 h−1; Group RC2: ropivacaine 0.08% 0.16 mg kg−1 h−1 + clonidine 0.08 mg kg−1 h−1; or Group RC3: ropivacaine 0.08% 0.16 mg kg−1 h−1, + clonidine 0.12 μg kg−1 h−1. Further details are given in the original article (1). No difference in overall heart rate or arterial blood pressure levels could be detected between the four study groups during the 48-h observation period. However, the systolic blood pressure variability, measured as the coefficient of variation (CV%) as described by Ghignone et al. (2) was significantly lower than in groups RC2 and RC3 compared with the other two groups (P < 0.001) (Table 1) (Fig. 1). No such difference was observed regarding heart rate variability (Table 1).Table 1: Intrapatient Variability of Hemodynamic VariablesFigure 1: Individual systolic blood pressure recordings in patients receiving a postoperative epidural infusion of either plain ropivacaine 0.1% (group R) or a co-infusion of ropivacaine 0.08% + clonidine 0.12 μg kg−1 h−1 (group RC3). Please note the difference in individual variability and the lack of difference regarding overall blood pressure levels between the two groups.The improved arterial blood pressure stability we observed associated with epidural clonidine administration is most likely explained by two interacting mechanisms. First, systemic uptake of clonidine from the epidural space into the systemic circulation will cause secondary interactions with centers in the brain stem (e.g., locus coeruleus and the vasomotor center) that affect central sympathetic discharge. Second, epidural clonidine in the dose range of 0.08–0.12 μg −1 h−1 is associated with improved postoperative pain relief (1). A reduced nociceptive input is likely to result in reduced blood pressure variability due to a reduction of the pain-generated stress response. However, if improved pain relief would be the main mechanism behind the observed reduction of blood pressure variability, then it is difficult to explain why heart rate variability did not show a similar pattern. Although strict cardiovascular control might not be essential after urogenital surgery in children, improved hemodynamic stability could be of potential benefit in other clinical situations (e.g., after major thoracic or abdominal surgery). We have previously shown that the bioavailability of clonidine is not restricted by epidural administration (3). Thus, one could postulate a similar hemodynamic effect if clonidine instead was administered as an intravenous infusion. Intravenous administration of clonidine would obviously make this property of clonidine useful in situations where epidural administration of clonidine is not an option (i.e., neurosurgery). H. T. G. Bergendahl P. A. Lonnqvist P. De Negri G. Ivani S. Eksborg

Cardiovascular effects of intravenous administration of clonidine in conscious cats

We previously reported that cardiovascular effects elicited by intracerebroventricular (i.c.v.) administration of clonidine result from stimulation of central α 2-adrenergic and/or H 2-histaminergic receptors, but not via activation of I 1-imidazoline receptors in conscious cats. In this study, we investigated the effects on arterial blood pressure (MAP) and heart rate (HR) following an intravenous (i.v.) administration of clonidine using conscious cats. Injection of clonidine (2–10 μg/kg i.v.) elicited a decrease in mean arterial pressure (MAP) and heart rate (HR) dose-dependently. The dose of 10 μg/kg of clonidine decreased MAP and HR by 30±4 mmHg and 62±15 bpm, respectively. Intravenous or i.c.v. pretreatment with yohimbine, the α 2-adrenoceptor and 5-HT 1A receptor antagonist, blocked the cardiovascular responses to a subsequent i.v. injection of 10 μg/kg clonidine. However, i.v. or i.c.v. preadministration of cimetidine, the H 2-histamine receptor antagonist, failed to antagonize the decreases in MAP and HR to a subsequent i.v. injection of 10 μg/kg clonidine. In addition, i.c.v. or i.v. pretreatment with the I 1-imidazoline receptor blocker, efaroxan, failed to inhibit the cardiovascular effects of an i.v. administration of clonidine. These results demonstrate that i.v. clonidine evokes decreases in MAP and HR possibly via central α 2-adrenoceptor and/or 5-HT 1A receptors and not through H 2-histamine or I 1-imidazoline receptors.

Modifications in the distribution of met-enkephalin in the pons of the cat, following the intravenous administration of clonidine: an immunocytochemical experimental study.

The distribution of met-enkephalin in the cat and its modifications following the stimulation by intravenous clonidine, was studied with indirect immunocytochemical techniques. We observed a decrease in the immunoreactivity of met-enkephalin following the administration of clonidine, relative to the controls, in the following structures: locus coeruleus, nucleus cuneformis, formatio reticularis, nucleus gigantocellularis, nucleus reticularis lateralis, nucleus reticularis, nucleus reticularis parvocellularis, nucleus sensorius superior n. trigemini, nucleus raphes, substantia grisea periventricularis, nucleus eminentiae teretis, colliculus inferior, nucleus motorius n. trigemini, nucleus tracto spinalis n. trigemini, tractus spinalis n. trigemini and nucleus tracto mesencephalici n. trigemini. These experimental observations link the immunoreactivity changes to the structures that are associated with the direct action of clonidine and conclude that the pars metencephalinergicus of the efferent pontine pathway of pain is in morpho-functional relationship with the analgesia produced by clonidine; an analgesic of an endogenous opiate character.

Internal jugular venous spillover of noradrenaline and metabolites and their association with sympathetic nervous activity.

It is recognized that the brain plays a pivotal role in the maintenance of blood pressure and the control of myocardial function. By combining direct sampling of internal jugular venous blood with a noradrenaline isotope dilution method, for examining neuronal transmitter release, and microneurographic nerve recording, we were able to quantify the release of central nervous system noradrenaline and its metabolites and investigate their association with efferent sympathetic nervous outflow in healthy subjects and patients with pure autonomic failure. To further investigate the relationship between brain noradrenaline, sympathetic nervous activity and blood pressure regulation we examined brain catecholamine turnover, based on the internal jugular venous overflow of noradrenaline and its principal central nervous system metabolites, in response to a variety of pharmacological challenges. A substantial increase was seen in brain noradrenaline turnover following trimethaphan, presumably resulting from a compensatory response in sympathoexcitatory forebrain noradrenergic neurones in the face of interruption of sympathetic neural traffic and reduction in arterial blood pressure. In contrast, reduction in central nervous system noradrenaline turnover accompanied the blood pressure fall produced by intravenous clonidine administration, thus representing the blood pressure lowering action of the drug. Following vasodilatation elicited by intravenous adrenaline infusion, brain noradrenaline turnover increased in parallel with elevation in muscle sympathetic nervous activity. While it is difficult to assess the source of the noradrenaline and metabolites determined in our studies, available evidence implicates noradrenergic cell groups of the posterolateral hypothalamus, amygdala, the A5 region and the locus coeruleus as being involved in the regulation of sympathetic outflow and autonomic cardiovascular control.

Catecholamine Metabolites in Internal Jugular Plasma: A Window into the Human Brain

Publisher Summary From recent research it is clear that the old idea of brain noradrenergic neurons subserving a predominantly sympathoinhibitory role is no longer tenable. The substantial increase in brain norepinephrine (NE) turnover following trimethaphan presumably results from a compensatory response in sympathoexcitatory forebrain noradrenergic neurons in the face of interruption of sympathetic neural traffic and reduction in arterial blood pressure, while the reduction in central nervous system (CNS) NE turnover in response to intravenous clonidine administration underlies the blood pressure-lowering action of the drug. Following the characterization of NE as the sympathetic neurotransmitter and the subsequent finding of a direct relationship between rates of sympathetic nerve firing and neurotransmitter release, the potential to use NE washout, or spillover to plasma, as an index of sympathetic nervous function is well established. Recent research extends this reasoning to CNS neurons and suggests the utility of using direct internal jugular vein blood sampling techniques in the assessment of central nervous system neuronal activity, by demonstrating a reduction in 3-methoxy-4-hydroxyphenylglycol (MHPG) jugular venous overflow from the brain of stump-tailed monkeys following clonidine administration. The clinical application of such methodology, however, is in line with current advancement.

Rebound Hypertension and Acute Withdrawal Associated with Discontinuation of an Infusion of Epidural Clonidine

A small percentage of patients with cancer pain suffer from refractory pain despite aggressive therapy. 1 Intraspinal administration of opioids and local anesthetic agents may be helpful in such settings, but their use may be limited by side effects such as motor block and hemodynamic instability. 2,3 Clonidine is a centrally acting α 2 -adrenergic agonist with established analgesic effects 4,5 and has synergistic effects with spinal opioids 6,7 and spinal local anesthetics. 8,9 Epidural clonidine produces analgesia by a spinal mechanism in patients after surgery and in those with cancer pain, 10 and it appears to be an effective treatment for severe cancer pain in patients for whom other treatments are ineffective. 11 Although the risk of acute withdrawal and rebound hypertension is well recognized with sudden cessation of systemically administered clonidine, 12 no such reports exist with regard to epidurally administered clonidine. We describe a case of acute withdrawal and rebound hypertension after abrupt cessation of epidural clonidine in a patient with intractable cancer pain.

Comparison of Intravenous and Epidural Clonidine for Postoperative Patient-Controlled Analgesia

Both epidural and intravenous clonidine are used to provide postoperative analgesia, but in predetermined doses. This double-blind randomized study was designed to 1) determine the clonidine dose inducing pain relief after major orthopedic surgery, when controlled by patient, either intravenously or epidurally; and 2) assess whether these two administration routes are clinically equivalent. At the first complaint of pain after scoliosis correction, patients received an initial dose of 8 micrograms/kg clonidine during 30 min either intravenously (n = 12) or epidurally (n = 12). Then, clonidine was given using a patient-controlled analgesia pump via the corresponding administration route. In both cases, the bolus dose was set at 30 micrograms and the lockout interval at 15 min. Pain (0-100 scale), clonidine requirements, sedation (0-4 scale), and hemodynamics (by fiberoptic pulmonary artery catheter) were measured before and 15, 30, 120, 240, 360, 480, and 600 min after the loading dose was started. Plasma clonidine concentrations and arterial blood gases were determined at the 15th, 30th, 240th, and 480th min. Self-administered and total clonidine doses were larger in the intravenous group than in the epidural group (at 600 min: 372 +/- 110 vs 235 +/- 144 micrograms, and including the initial dose, 814 +/- 114 vs 652 +/- 187 micrograms; mean +/- SD). Clonidine administration resulted in pain relief and sedation in both groups but, for comparable pain relief, sedation scores were lower in the epidural group. No intergroup differences in hemodynamic data were observed, although the decrease in blood pressure occurred earlier in the intravenous group. Plasma clonidine concentrations were higher in the intravenous group than in the epidural group (2.5 +/- 0.6 vs 1.5 +/- 0.5 ng/mL after the initial dose and 2.1 +/- 0.5 vs 1.5 +/- 0.4 ng/mL during self-administration; mean +/- SD). We conclude that analgesia can be achieved postoperatively by both epidural and intravenous clonidine administration. The epidural route is associated with significant reductions in self-administered clonidine dose, and thus in the plasma clonidine concentration, and the level of sedation.(ABSTRACT TRUNCATED AT 250 WORDS)

Disynaptic group I excitation of synergist ankle extensor motoneurones during fictive locomotion in the cat.

1. Intracellular recording from medial gastrocnemius (MG) motoneurones was used to examine postsynaptic potentials produced by electrical stimulation of the plantaris nerve at group I strength at rest and during fictive locomotion. Fictive locomotion was evoked by stimulation of the midbrain locomotor region (MLR) in decerebrate cats or in decerebrate, acute low-spinal cats by perineal stimulation following intravenous administration of clonidine and naloxone. 2. In both MLR and spinal fictive locomotor preparations, stimulation of plantaris nerve group I afferents at rest evoked short-latency (< 2 ms) IPSPs in MG motoneurones. During the extensor phase of MLR-evoked locomotion, the same stimulation produced short-latency (1.6-1.8 ms) EPSPs. Such latencies suggest mediation by one interneurone interposed between plantaris nerve group I afferents and MG motoneurones. Non-monosynaptic, short-latency excitation was not seen at rest nor during the flexion phase of the step cycle. 3. Group I EPSPs during the extensor phase of MLR-evoked locomotion were evoked by stimulation at intensities ranging from 1.4-2 times threshold (T). The effectiveness of stimulation intensities < 1.5 T suggests that activation of group II afferents is not required to evoke disynaptic excitation. Selective activation of group Ia afferents by stretches of the Achilles tendon also produced disynaptic EPSPs during extension. 4. During fictive locomotion in spinal animals pretreated with clonidine, short-latency group I EPSPs were not seen but group I IPSPs recorded at rest disappeared or were greatly attenuated. The failure of depolarizing current to reveal group I IPSPs suggests that fictive locomotion involves an inhibition of the inhibitory interneurones that operate at rest. In both clonidine-treated spinal and MLR preparations, trains of stimuli at group I strength evoked longer-latency and slowly rising potentials that were more prominent during the flexor phase of fictive locomotion. 5. These results show a reduction in short-latency group I inhibition of synergists in both MLR and clonidine-treated spinal preparations during fictive locomotion. In addition, activation of group I afferents evokes short-latency excitation of synergists during extension in the MLR preparation. Such excitatory reflexes activated by ankle extensor group Ia and Ib afferents may form an excitatory feedback system, reinforcing on-going extensor activity during the stance phase of the step cycle.

Effects of gender and diagnosis on growth hormone response to clonidine for major depression: a large-scale multicenter study.

The authors' goal was to establish, in a large multicenter sample of patients classified according to gender and menopausal status, if the growth hormone (GH) response to clonidine discriminated patients with episodes of major depression from patients with episodes of minor depression. The GH response to intravenous clonidine administration (150 micrograms) was compared in 71 male and 140 female patients with major depressive episodes and 47 male and 53 female patients with minor depressive episodes. These patients were diagnosed according to Research Diagnostic Criteria. Differences in the GH response to clonidine between diagnostic groups occurred only between male patients. These results were found in the group as a whole and in each center. The GH responses to clonidine of premenopausal women differed significantly from those of postmenopausal women in each diagnostic group. These results confirm that gender and menopausal status are of the utmost importance in the interpretation of the clonidine GH test.

Expression of beta-adrenoceptors on circulating mononuclear cells in hypertensives and normotensives before and after reduction of central sympathetic outflow by clonidine.

We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells (PBMCs) in normotensives (NT) and hypertensives (HT), before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine, there was a decrease in blood pressure and plasma noradrenaline (NA) and adrenaline (Ad) levels, with an increase in growth hormone (GH) levels, in both NT and HT. There was no difference in basal beta-adrenoceptor densities on PBMCs between NT and HT. After clonidine at 30 and 60 min, there was an increase in beta-adrenoceptor density associated with a low affinity in NT. In HT, no changes were observed. The increased beta-adrenoceptor densities on PBMCs in NT after clonidine, returned to baseline values after 2 h. Short term up-regulation of beta-adrenoceptors on PBMCs in NT after clonidine is accompanied by a fall in blood pressure (BP) and plasma levels of catecholamines. The changes may represent a compensatory mechanism reflecting a rapid externalization-activation of adrenoceptors residing on the internal surface of the membranes with a change of the coupling ability between the receptor and the catalytic component. In HT, although the haemodynamic and neurohormonal response to clonidine was similar to NT, short term upregulation of receptors did not occur. The lack of such response may mirror a form of regulatory dysfunction of beta-adrenoceptors in HT.

PHF-1 immunopositive dystrophic neurites are preferentially associated with thioflavine positive β-pleated plaques and not diffuse amyloid plaques : B.J. Cummings, C.J. Pike and C.W. Cotman. IRU in Brain Aging and Dementia, Department of Psychobiology, University of California, Irvine, CA 92717-4550 USA

Recent studies in the rat have demonstrated that at least two populations of sympathoexcitatory reticulospinal neurons reside in the nucleus reticularis rostroventrolateralis. It appears that only one of these populations consists of C1 adrenergic neurons. The present study used both double-labeling (one retrograde tracer and immunohistochemistry) and triple-labeling (two retrograde tracers and immunohistochemistry) to determine if C1 adrenergic neurons, which are immunoreactive for phenylethanolamineN-methyltransferase, exhibit a projection pattern that is sufficiently unique to permit the electrophysiological discrimination between C1 adrenergic and non-adrenergic neurons in the nucleus reticularis rostroventrolateralis. Double-labeling experiments indicated that 71% (range: 53–80) ofphenylethanolamine-N-methyltransferase-immunoreactive neurons in the nucleus reticularis rostroventrolateralis could be retrogradely labeled from the thoracic cord, as were 76% (range: 67–94) following tracer injection in the central tegmental tract at pontine levels. Triple-labeling experiments indicated that 88% (range: 82–93) of nucleus reticularis rostroventrolateralis neurons with projections to both spinal cord and central tegmental tract werephenylethanolamine-N-methyltransferase-immunoreactive.Single-unit recording, in nucleus reticularis rostroventrolateralis, was used to identify antidromic potentials elicted from stimulation sites in the spinal cord and/or central tegmental tract. Since clonidine is known to reduce central adrenaline turnover, sensitivity to this drug was used to identify putative adrenergic neurons. Twenty-six nucleus reticularis rostroventrolateralis neurons with axonal projections to both the ipsilateral spinal cord and the central tegmental tract were recorded in halothane-anesthetized rats. All these cells were barosensitive, pulse-modulated, and 16 of the 16 cells tested exhibited a66 ± 8% reduction in activity upon the intravenous administration of clonidine (20 μg/kg). Most (13 out of 16) exhibited a strong respiratory modulation. The conduction velocity of their spinal collateral was generally low (0.9 ± 0.1m/s) and their firing rate moderate (7.4 ± 1.2spikes/s). Forty-three nucleus reticularis rostroventrolateralis cells with axonal projections exclusively to the thoracic cord were studied for comparison. These cells were strongly barosensitive and pulse-synchronous, had a high discharge rate (25 ± 3spikes/s) and a moderate conduction velocity (3.4 ± 0.3m/s). Only one of the 15 cells tested was inhibited by clonidine and only two to these 15 cells exhibited a detectable respiratory modulation.Thus barosensitive nucleus reticularis rostroventrolateralis neurons with axonal projections to both the spinal cord and the central tegmental tract likely belong the the C1 adrenergic cell group. It is concluded that this subgroup of adrenergic neurons probably subserves a vasomotor function.