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PubMed2026

The effect of dexmedetomidine in mechanically ventilated patients with sepsis and septic shock: a meta-analysis of randomized controlled trials.

PURPOSE: Dexmedetomidine (DEX) is a central sympatholytic with sedative properties widely used in critically ill patients. However, its effects in patients with sepsis and septic shock remain controversial. This meta-analysis evaluated the efficacy and safety of DEX compared to other sedatives in mechanically ventilated patients with sepsis and septic shock. METHODS: A systematic search was conducted across PubMed, Embase, Scopus, and Cochrane Library from inception through May 1, 2025 for randomized controlled trials comparing DEX with other sedatives or placebo in mechanically ventilated patients with sepsis and septic shock. Primary outcomes included overall mortality and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes encompassed duration of mechanical ventilation (MV), length of stay in Intensive Care Unit (ICU), incidence of hypotension and bradycardia. RESULTS: Fifteen studies involving 3,882 patients (1,945 in the DEX group, 1,937 in the control group) were included. DEX was demonstrated no significant differences compared to other sedatives or placebo in overall mortality (Risk Ratio [RR] 0.98, 95% Confidence Interval [CI] 0.90 to 1.07, p = 0.71, I2 = 0%), SOFA scores (Mean Difference [MD] - 0.14, 95% CI -0.81 to 0.52, p = 0.67, I2 = 0%), length of stay in ICU (MD -0.32, 95% CI -1.69 to 1.06, p = 0.65, I2 = 77%), or incidence of hypotension (RR 1.15, 95% CI 0.81 to 1.62, p = 0.44, I2 = 14%). However, DEX significantly reduced the duration of MV (MD -0.54, 95% CI -0.98 to -0.10, p = 0.02, I2 = 25%) but was associated with an increased incidence of bradycardia (RR 1.67, 95% CI 1.22 to 2.28, p = 0.001, I2 = 0%). CONCLUSIONS: In mechanically ventilated patients with sepsis and septic shock, DEX shortened duration of MV but was associated increased bradycardia risk. No mortality or organ dysfunction benefits were observed. These findings suggest DEX is a reasonable therapeutic option to facilitate earlier ventilator weaning in selected patients (particularly those without shock), but careful monitoring for cardiovascular adverse effects is warranted.

Humans↗
PubMed1978

Persistence of an amine uptake system in cultured rat sympathetic neurons which use acetylcholine as their transmitter.

Cultures of dissociated rat superior cervical ganglion neurons (SCGN) were treated with the sympatholytic agent, guanethidine. When treated within the first couple of weeks in vitro, the neurons were rapidly destroyed. The cells grew less susceptible to the toxic effects of guanethidine with age in vitro. Moreover, the apparent affinity, Km, of the transport molecule for norepinephrine (NE) and guanethidine remained essentially unchanged between 2 and 7 wk in culture, as did the maximum velocity of transport (Vmax). This is at a time when previous studies have shown these neurons to be using acetylcholine (ACh) as their neurotransmitter. Cultures which were grown without supporting cells and from which cholinergic synaptic interactions were recorded physiologically were processed for autoradiography after incubation with [3H]NE. All cell bodies and processes seen had silver grains accumulated over them. These experiments show that sympathetic neurons in vitro maintain their amine uptake system relatively unchanged, even though they use ACh as their transmitter. The implications of these findings are discussed.

Acetylcholine↗
PubMed1988

Challenges in therapy of hypertension in the elderly.

Treating older hypertensive patients presents special challenges. The physiological effects of aging result in hemodynamic and pharmacokinetic changes. Geriatric patients are more likely to have concomitant diseases than younger patients. Treatment regimens should be individualized; monotherapy should be the goal. While most antihypertensive agents can be used, each class of drugs has advantages and disadvantages. Diuretics are both effective and inexpensive but their metabolic side effects (especially hypokalemia) may be quite serious in the geriatric population. Sympatholytics, beta-blockers, alpha-blockers, and direct vasodilators may not be tolerated. The angiotension-converting enzyme inhibitors, captopril and enalapril, are good choices because they have favorable hemodynamics, renin and nonrenin-dependent mechanisms of action and are associated with minimal biochemical alterations. In a recent multicenter study, captopril (25 mg twice daily) was given to 99 geriatric patients with seated diastolic blood pressure (BP) of 92-110 mm Hg. Patients whose blood pressures were not controlled after two weeks of therapy were randomized to either Capozide (captopril, 25 mg with 15 mg hydrochlorothiazide) or captopril, 50 mg twice daily. The average decrease in BP was 16.9/11.9 mm Hg; 75.8% of patients responded to treatment. Black and white patients had equal responses. Only five patients withdrew from the study due to adverse reactions, none of which was serious. Geriatric hypertensives should be treated. Because captopril and Capozide are well-tolerated, effective medications in elderly patients with mild, moderate, or severe hypertension, they should be considered as initial therapy for geriatric hypertension.

Aged↗
PubMed1989

Primary hypertension, neural tone, and behavior. Role in pressor responses to stress.

Patients with primary hypertension follow a hierarchical pattern of hemodynamic and neurohumoral responses to laboratory and environmental mental and physical stress. The stressor responses are regulated by the central and peripheral autonomic nervous system. The psychological and behavioral characteristics of these persons--for example, whether they conform to the Type A pattern of behavior, including hostility and anxiety--alter the magnitude and duration of their stress responses. For some patients, the magnitude of the neurohumoral activation can predict the effectiveness of therapy with sympatholytic and other types of drugs used to treat hypertension.

Animals↗
PubMed1999

I.v. lidocaine worsens histamine-induced bronchoconstriction in dogs.

We have assessed the effect of lidocaine (lignocaine) on histamine-induced bronchoconstriction by direct visualization with a superfine fibreoptic bronchoscope. Seven mongrel dogs were anaesthetized with pentobarbital (pentobarbitone) 30 mg kg-1 followed by 2 mg kg-1 h-1 and pancuronium 200 micrograms kg-1 h-1. The trachea was intubated with a tracheal tube containing a second lumen for insertion of a 2.2-mm fibreoptic bronchoscope. This allowed estimation of the bronchial cross-sectional area (BCA) of the third bronchial bifurcation of the right lung. We used NIH image, a public domain image processing and analysis program. Bronchoconstriction was produced with a bolus dose of histamine 10 micrograms kg-1 i.v. followed by continuous infusion of 500 micrograms kg-1 h-1. After 30 min the following i.v. doses of lidocaine were given: lidocaine 0 (saline), 0.01, 0.1, 1.0 and 10 mg kg-1 at 10-min intervals. BCA was assessed 90 s after each dose. Arterial blood sampling was performed for measurement of plasma catecholamines. Lidocaine 1.0 and 10 mg kg-1 significantly reduced histamine-decreased BCA from 69.7 (SEM 4.1)% to 59.8 (7.3)% and 34.3 (6.8)%, respectively. Plasma concentrations of catecholamines decreased significantly after lidocaine 10 mg kg-1 i.v. In addition, there was a significant correlation between percentage decreases in plasma concentrations of epinephrine (adrenaline) and norepinephrine (noradrenaline) and reduction in %BCA (epinephrine-BCA, P < 0.01, r = 0.674; norepinephrine-BCA, P < 0.01, r = 0.510). This study suggests that i.v. lidocaine may exacerbate histamine-induced bronchoconstriction by a sympatholytic effect. This may have therapeutic implications for patients with acute asthma or anaphylactic shock who may become dependent on circulating catecholamines.

Anesthetics, Intravenous↗
PubMed2006

Skin conductance monitoring compared with Bispectral Index to assess emergence from total i.v. anaesthesia using propofol and remifentanil.

BACKGROUND: Arousal after sevoflurane anaesthesia has been detectable by monitoring changes in skin conductance (SC) with similar accuracy as monitoring Bispectral Index (BIS). As SC monitoring detects changes in sympathetic tone, the measurements might be confounded by the sympatholytic properties of propofol, a component of total i.v. anaesthesia (TIVA). Therefore in this study, monitoring of SC during emergence from TIVA was compared with the monitoring of BIS. METHODS: Twenty-five patients undergoing plastic surgery were investigated. The number of fluctuations of SC per second (NFSC), BIS and haemodynamic variables [systolic blood pressure (SBP) and heart rate (HR)] were recorded simultaneously. The performance of the monitoring devices in distinguishing between the clinical states 'steady-state anaesthesia', 'first clinical reaction' and 'extubation' were compared using the method of prediction probability (Pk) calculation. RESULTS: BIS((R)) showed the best performance in distinguishing between 'steady-state anaesthesia' and 'first reaction' (Pk BIS 0.99 vs NFSC 0.80; P<0.01), and 'steady-state anaesthesia' and 'extubation' (Pk BIS) 1.00 vs NFSC 0.91; P<0.05); the time from first change of BIS or NFSC to a first clinical reaction was significantly longer for NFSC (median BIS 135 s vs NFSC 191 s; P<0.05). BIS and NFSC performed better in distinguishing between the investigated clinical states than SBP and HR. CONCLUSIONS: In this study, BIS was found to predict arousal with a higher probability but slower response times than NFSC in patients waking after TIVA.

Adult↗
PubMed1994

Visceral afferents: their contribution to 'sympathetic dependent' pain.

For 80 years the sympathetic nervous system has been implicated in certain human pains, notably causalgia and reflex sympathetic dystrophy. This assumption has led to the accepted concept of 'sympathetic dependent' pain. In this critical review, the evidence for this assumption is assessed. It is found that the clinical phenomena suggesting sympathetic nerve involvement may be more satisfactorily attributed to effects of neuropeptides released from afferent C-fibres. The evidence also demonstrates that the effects resembling sympathetic dysfunction relate neither to the pain nor to pain relief following sympathetic blockade. The techniques and results of sympathetic blockade have rarely been adequately evaluated, and the apparent efficacy, specificity and mode of action of peripheral sympatholytic drugs are questioned. An alternative explanation is proposed: that visceral afferents subserve a number of human pains, including those that have been considered sympathetically mediated. Problems of terminology are discussed; use of the term 'visceral afferent' is clarified and broadened to include afferents, particularly those related to blood vessels, which travel within autonomic nerves, in addition to the classical visceral afferent innervation of the organs of the great body cavities. The clinico-anatomical evidence reviewed here indicates that this general and widespread system of afferents could subserve certain pains. The relationship between visceral afferents, somatic afferents and autonomic efferents is outlined, and support is found for the unitary nature of the sensory system envisaged by Langley. Conflicting results from experiments on animals and clinical studies in man on the pain-subserving properties of visceral afferents are summarized; these confirm that visceral afferents can, at least on occasions in man, mediate pain not considered typically 'visceral'. This conclusion receives support from a number of clinical observations: not only are diseases of the autonomic nervous system painless, but damage to previously painless autonomic nerves can generate pain, as illustrated by several different conditions; pain from diseases other than of the viscera of the great cavities and which involves the widespread visceral afferents may be alleviated by sympathetic blockade, presumably since afferents travelling within autonomic fibres are simultaneously blocked; and diseases which impair the function of autonomic nerves may be unexpectedly painless. The central nervous system sequelae following involvement of visceral afferents are outlined and found to be relevant to phenomena sometimes seen with causalgia and related conditions: spread of pain; mirror involvement; associated features such as involuntary movements; and referred pain. Visceral afferents are generally clinically silent unless damage occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1993

Pathophysiology and clinical aspects of hypertensive hypertrophy.

Individuals with hypertension and electrocardiographic (ECG) evidence of left ventricular hypertrophy (LVH) have a 10-fold greater risk of developing cardiac failure than hypertensives without ECG evidence of LVH. LVH in hypertension is characterized by myocardial fibrosis and structural changes to the small intramural arteries. Hypertensives with or without LVH have reduced coronary vasodilator reserve due to hypertensive disease of small coronary arteries. Prognosis of arterial hypertension is largely determined by cardiac complications. The aim of treatment of hypertensive heart disease is to reverse myocardial hypertrophy in order to prevent progression to hypertensive heart failure, as well as reversal of the hypertensive disease of small coronary arteries in order to improve coronary reserve. On the development of hypertensive heart failure, administration of digitalis, diuretics and angiotensin converting enzyme (ACE) inhibitors should be initiated. Although regression of LVH can be induced by dihydropyridine calcium channel blockers, ACE inhibitors and sympatholytic substances, clinical evidence of the reversal of hypertensive disease of small coronary arteries has still to be established.

Adrenergic beta-Antagonists↗
PubMed1987

Use of diprafenone, a new potent propafenone-analogue, in acute experimental myocardial ischaemia and infarction.

Diprafenone (D) is a new class I c antiarrhythmic agent, structurally similar to propafenone. We assessed its antiarrhythmic and anti-fibrillatory effects during acute coronary occlusion and reperfusion and the underlying mechanisms of action by epicardial mapping of the conduction delay; also the effects of D on stimulus-induced ventricular tachycardia 18-24 h after permanent coronary occlusion were assessed. Experiments were performed on 32 mongrel dogs with temporary coronary occlusion lasting 20 min and subsequent reperfusion. Control ligations in 16 animals were compared to ligations after pretreatment with D (2 mg kg-1) in 6 dogs. In another 10 dogs a permanent coronary occlusion was performed and the inducibility of ventricular tachycardia was assessed by programmed stimulation before and after D (2.4 mg kg-1). Following D the incidence of ventricular arrhythmias including rapid ventricular tachycardias was not reduced during acute coronary occlusion, but even enhanced in some animals, whereas the frequency of ventricular fibrillation was diminished. No significant difference was observed following reperfusion. Conduction delay in the ischaemic area increased significantly during both phase Ia and Ib following pretreatment with D. During reperfusion conduction delay was significantly prolonged in the D group. At 18-24 h after permanent coronary occlusion the new compound proved to be highly effective in suppressing stimulus-induced ventricular tachycardia. During acute coronary occlusion D diminished the incidence of ventricular fibrillation. D is similar to other class Ic compounds; however, there are some important differences with respect to its additional beta-sympatholytic activity.

Acute Disease↗
PubMed1983

Effects of low-dose antihypertensive therapy in elderly patients with predominant systolic hypertension.

Patients over 60 years of age (M = 70 years) with the predominant systolic form of essential hypertension (systolic blood pressure greater than 160 mm Hg; diastolic blood pressure less than 100 mm Hg) were treated with a combination of low doses of the diuretic chlorthalidone and the centrally-acting sympatholytic agent clonidine. In this randomized double-blind study, patients received either active treatment (n = 14) or placebo (n = 16). Baseline systolic blood pressure in the treatment group averaged 172 mm Hg and was controlled (fall in systolic blood pressure to less than 140 mm Hg or by at least 10%) in 13 of the 14 patients; in eight patients, control was achieved with a single daily dose (given at night) of the clonidine (.1 mg)-chlorthalidone (15 mg) combination. The active drug was significantly superior to placebo in decreasing systolic blood pressure. Changes measured in the standing position did not differ from those in the supine position. Side effects were mild and transient for both the placebo and the treatment groups. Low-dose combination therapy appears to be a highly effective approach for the management of older patients with predominant systolic hypertension of mild-to-moderate degree.

Aged↗
PubMed1991

Antihypertensive effect of cicletanine is exaggerated in NaCl-sensitive hypertension.

Cicletanine (CIC), a furopyridine derivative, lowers blood pressure in hypertensive animals and humans. We have previously identified an NaCl-sensitive substrain of spontaneously hypertensive rat (SHR-S) that displays enhanced sensitivity to the depressor effects of exogenous atrial natriuretic peptide (ANP) when fed a high NaCl diet. The current study tested the hypotheses that CIC has an exaggerated antihypertensive effect in NaCl-supplemented SHR-S and that this effect might be ANP dependent. CIC (40 mg/kg/day) or vehicle was administered by gavage in a single daily dose for three weeks beginning immediately prior to initiation of 1% or 8% NaCl diets in seven-week-old male SHR-S. CIC significantly decreased mean arterial pressure (MAP) and the ratio of left ventricular and septum weight to body weight (LV + S/BW) in both 8% NaCl- and 1% NaCl-fed SHR-S. The depressor effect of CIC was greater in the 8% NaCl group (-26 mmHg) than in the 1% NaCl group (-13 mmHg). CIC was associated with significant reduction in RAP in the 8% NaCl group but not in the 1% NaCl group. Neither CIC treatment nor 8% NaCl significantly altered plasma ANP or cyclic guanosine monophosphate (GMP) levels in plasma, aorta, or kidney. CIC was associated with significant decreases in plasma norepinephrine (NE) levels in the 1% NaCl group but not in the 8% NaCl group. The data demonstrate that the antihypertensive effect of CIC is exaggerated in NaCl-sensitive hypertension. The antihypertensive effect of CIC appears not to be related to ANP or cyclic GMP but may be related to a combination of a sympatholytic and natriuretic/diuretic effects in SHR-S.

Animals↗
PubMed1996

The effects of alpha 2-adrenergic stimulation with mivazerol on myocardial blood flow and function during coronary artery stenosis in anesthetized dogs.

The central sympatholytic effect of alpha 2 agonists may be beneficial during myocardial ischemia, but could be opposed by their peripheral vasoconstrictive effect. We studied the effects of mivazerol during periods of moderate coronary artery stenosis in anesthetized dogs. Mivazerol decreased heart rate (from 125 +/- 6 to 106 +/- 6 bpm) and cardiac output (from 4.4 +/- 0.6 to 1.8 +/- 0.2L/min) under normal conditions, while mean arterial pressure did not change. Mivazerol reduced blood flow in nonischemic myocardium and in the ischemic epicardial layer, but blood flow was preserved in the ischemic midmyocardial and subendocardial layer. Mivazerol had no effect on myocardial oxygen extraction during the stenoses, and regional myocardial oxygen consumption was unchanged. However, mivazerol decreased myocardial oxygen demand from 4.51 +/- 0.51 to 3.17 +/- 0.24 mumol.min-1.g-1, thereby reducing oxygen deficiency of ischemic myocardium to values significantly lower than in the placebo group (from 1.07 +/- 0.32 to 0.47 +/- 0.41 mumol.min-1.g-1). Mivazerol had no effect on myocardial lactate production during the stenoses. We conclude that mivazerol reduced myocardial oxygen demand while blood flow was preserved in the inner layers of ischemic myocardium.

Adrenergic alpha-Agonists↗
PubMed1998

The effect of clonidine or midazolam premedication on perioperative responses during ketamine anesthesia.

UNLABELLED: The use of ketamine as a sole anesthetic induces marked central sympathetic stimulation, causing increased heart rate, blood pressure (BP), and oxygen consumption (VO2). Both alpha 2-agonists and benzodiazepines have been used to attenuate these potentially harmful ketamine-induced responses. This double-blind, randomized, placebo-controlled study was designed to compare the perioperative metabolic, hemodynamic, and sympathoadrenal responses to IM clonidine (2 micrograms/kg) and midazolam (70 micrograms/kg) premedication during ketamine anesthesia. VO2 was measured continuously using indirect calorimetry in 30 ASA physical status I patients. The patients received ketamine, mivacurium, and fentanyl for the induction of anesthesia. Anesthesia was maintained using a ketamine infusion and fentanyl boluses i.v. Preoperatively, both VO2 and BP decreased significantly after the administration clonidine and midazolam compared with placebo (P < 0.01). Intraoperatively, VO2 was higher in the midazolam group than in the placebo and clonidine groups (P < 0.05). Postoperatively, there were no significant differences in BP and VO2, although they stayed at lower level in the clonidine group during the whole postoperative period. Clonidine decreased pre- and postoperative plasma catecholamine concentrations (P < 0.05). Our results indicate that a midazolam-ketamine combination may induce potentially harmful metabolic stimulation, whereas the sympatholytic effects of clonidine on ketamine-anesthetized patients may be beneficial, as perioperative VO2 was decreased. IMPLICATIONS: Ketamine causes sympathetic stimulation with an ensuing increase in oxygen consumption. Anticipating that clonidine might attenuate this response, we measured oxygen consumption in patients undergoing surgery during ketamine anesthesia. Patients treated with a clonidine-ketamine combination had lower intra- and postoperative oxygen consumption than those treated with a midazolam-ketamine combination.

Adjuvants, Anesthesia↗
PubMed1998

The mechanism of alpha2-adrenergic inhibition of sympathetic ganglionic transmission.

UNLABELLED: Alpha2-adrenergic agonists produce analgesia and reduce hemodynamic stress through central and peripheral mechanisms, but the effect of adrenergic agonists on pre- and postganglionic sites has not yet been clarified. In this study, we examined the effects of dexmedetomidine (DMT), an alpha2-agonist, on neural conduction and neurotransmitter release in sympathetic ganglia. The stellate ganglia from 48 mongrel dogs were isolated, desheathed, and superfused with Krebs' solution. Compound action potentials were evoked, and chromatography was used to detect acetylcholine released by preganglionic stimulation in the presence or absence of DMT. To further elucidate the mechanism of alpha2 effects, DMT was applied in combination with the alpha2-antagonist atipamezole (AT) or the imidazoline antagonist idazoxan (ID). In other experiments, DMT was applied in the presence of exogenous nicotinic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide or muscarinic stimulation with (+)cis-dioxolane. DMT dose-dependently inhibited synaptic transmission with a 50% effective dose of 71.6 (26.0-174.3) microM. Neurotransmitter release was reduced 25% by 70 microM DMT during low-frequency (0.4 Hz) stimulation, but this effect was abolished at higher frequency (5 Hz) stimulation. AT but not ID blocked the inhibitory action of DMT. DMT inhibited the excitatory postsynaptic response to exogenous muscarinic stimulation but not nicotinic stimulation. These results indicate that alpha2-receptor activation depresses ganglionic transmission through postsynaptic inhibition of muscarinic stimulation, although reduction of neurotransmitter release through a presynaptic autofeedback mechanism is also involved. IMPLICATIONS: This article provides novel insights into the mechanism of drug action of alpha2-receptor agonists in the sympathetic ganglia of dogs by directly measuring the relative contribution of pre- and postganglionic receptors. Our study indicates that the central sympatholytic effects of alpha2-adrenoceptor stimulation are augmented by peripheral inhibition of ganglionic transmission.

Acetylcholine↗
PubMed1992

Intrathecal clonidine and the response to hemorrhage.

Intraspinally administered alpha 2-adrenergic agonists are being examined for postoperative analgesia, yet their effects on the hemodynamic response to acute hemorrhage have not been examined. In this study chronically prepared conscious sheep received thoracic intrathecal saline or clonidine 300 micrograms followed in 15 min by rapid removal of 1,000 ml blood. In saline-treated ewes blood pressure was maintained and heart rate steadily increased during hemorrhage of up to 700 ml blood, with further blood removal resulting in rapid decreases in both variables. In contrast, heart rate never increased and blood pressure was maintained only up to 400 ml blood loss in animals receiving intrathecal clonidine. Compared to saline controls, clonidine did not alter blood pressure or heart rate at the end of hemorrhage or during blood pressure restitution during the next hour. Clonidine inhibited the increase in plasma epinephrine at the end of hemorrhage without altering plasma norepinephrine, vasopressin, renin, or atrial natriuretic factor. Intrathecal idazoxan, a specific alpha 2-adrenergic antagonist, reversed clonidine's effect on blood pressure during hemorrhage. Intravenous DG-5128, a poorly lipid-soluble alpha 2-adrenergic antagonist, also reversed clonidine's effect and additionally completely blocked any reduction in blood pressure and heart rate during hemorrhage. These data suggest that intrathecal clonidine interferes with maintenance of blood pressure during hemorrhage, likely because of a spinal sympatholytic effect, but does not affect the ultimate decrease in blood pressure after rapid removal of 1,000 ml blood. This difference in effect during the two phases of hemorrhage can be explained by the relative importance of the sympathetic nervous system in each.

Adrenergic alpha-Antagonists↗
PubMed1993

The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: Dexmedetomidine is an alpha 2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. METHODS: The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 micrograms/kg by intravenous or intramuscular route in separate study sessions. RESULTS: The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 +/- 11% (mean +/- SD). After intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 +/- 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 micrograms/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10%. CONCLUSIONS: The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

Adrenergic alpha-Agonists↗
PubMed1997

Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury.

BACKGROUND: Ligation injury of the L5/L6 nerve roots in rats produces behavioral signs representative of clinical conditions of neuropathic pain, including tactile allodynia and thermal and mechanical hyperalgesia. In this model, intrathecal morphine shows no antiallodynic activity, as well as decreased antinociceptive potency and efficacy. This study was designed to explore the antinociceptive activity of intrathecal clonidine alone or in combination with intrathecal morphine (1:3 fixed ratio) in nerve-injured rats. The aims, with this study, were to use nerve-injured animals to determine: (1) whether the antinociceptive potency and efficacy of intrathecal clonidine was altered, and (2) whether the combination of intrathecal morphine and clonidine would act synergistically to produce antinociception. METHODS: Unilateral nerve injury was produced by ligation of the L5 and L6 spinal roots of male Sprague-Dawley rats. Sham-operated rats underwent a similar surgical procedure but without nerve ligation. Morphine and clonidine were given intrathecally through implanted catheters alone or in a 1:3 fixed ratio. Nociceptive responses were measured by recording tail withdrawal latency from a 55 degrees C water bath, and data were calculated as % maximal possible effect (%MPE). RESULTS: Morphine produced a dose-dependent antinociceptive effect in both sham-operated and nerve-injured rats. The doses calculated to produce a 50 %MPE (i.e., A50) (+/-95% confidence intervals [CI]) were 15 +/- 4.9 micrograms and 30 +/- 18 micrograms, respectively. Though morphine was able to produce a maximal response (100%) in sham-operated rats, the maximal response achieved in nerve-injured animals was only 69 +/- 21.9 %MPE. Clonidine produced a dose-dependent effect, with an A50 (+/-95% CI) of 120 +/- 24 micrograms in sham-operated rats. In nerve-ligated rats, clonidine produced a maximal effect that reached a plateau of 55 +/- 10.9 %MPE and 49 +/- 10.2 %MPE at 100 and 200 micrograms, respectively, preventing the calculation of an A50. In sham-operated rats, a morphine-clonidine mixture produced maximal efficacy, with an A50 (+/-95% CI) of 15 +/- 9.2 micrograms (total dose), significantly less than the theoretical additive A50 of 44 +/- 10 micrograms. In L5/L6 nerve-ligated rats, the morphine-clonidine combination produced maximal efficacy, with an A50 (+/-95% CI) of 11 +/- 5.4 micrograms (total dose), which was significantly less than the theoretical additive A50 of 118 +/- 73 micrograms, indicating a synergistic antinociceptive interaction. The intrathecal injection of [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) produced A50 values of 0.23 microgram (range, 0.09-0.6) and 0.97 microgram (range, 0.34-2.7) in sham-operated and ligated rats, respectively. Phentolamine (4 mg/kg, intraperitoneally) produced no antinociceptive effect alone and attenuated, rather than enhanced, the effect of morphine in both groups of rats. CONCLUSIONS: These data show that: (1) clonidine, like morphine, loses antinociceptive potency and efficacy after nerve ligation injury, and (2) strongly suggest that a spinal combination of morphine and clonidine synergize under conditions of nerve injury to elicit a significant antinociceptive action when either drug alone may be lacking in efficacy. It is unlikely that the synergy of morphine with clonidine is due to an attenuation of spinal sympathetic outflow by clonidine, because the sympatholytic agent phentolamine produced an opposing effect on morphine antinociception. The data suggest that combinations of morphine and clonidine may prove useful in controlling pain in patients with neuropathic conditions.

Adrenergic alpha-Agonists↗
PubMed2005

Effect of alpha2B-adrenoceptor polymorphism on peripheral vasoconstriction in healthy volunteers.

BACKGROUND: Alpha-2B adrenoceptor is the vasoconstrictive subtype in the mouse. Human alpha2B-AR deletion (D) allele has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction on alpha2 activation. The goal of this study was to test the hypothesis that alpha2B-adrenoceptor activation induces enhanced vasoconstriction in carriers of the DD genotype, compared with carriers of the insertion/insertion (II) genotype. METHODS: The authors administered increasing doses of dexmedetomidine (targeting plasma concentrations of 0.15, 0.3, 0.6, and 1.2 ng/ml) to 16 healthy young volunteers (8 carrying the alpha2B DD genotype, 8 carrying the II genotype) in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger, finger blood flow by venous occlusion plethysmography, and hemodynamic variables. RESULTS: All concentration of dexmedetomidine increased light transmitted through the finger (vasoconstriction) and systolic blood pressure and decreased heart rate in both groups (P < 0.001 for all). Dexmedetomidine reduced finger arterial inflow only in the DD group (P < 0.001). Dexmedetomidine had no effect on finger venous outflow or venous capacitance. There were no significant differences between the II and DD groups in any of the variables. CONCLUSIONS: The results of this study confirm the alpha2 agonist induced vasomotor and hemodynamic effects in peripheral vasculature. However, the results do not support the hypothesis that alpha2B-adrenoceptor polymorphism has an effect on peripheral vasoconstriction in humans.

Adrenergic alpha-Agonists↗