Caudal clonidine for postoperative analgesia in adults.
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We have assessed the analgesic efficacy and side effects of caudally administered clonidine in a prospective, randomized, double-blind, placebo-controlled study. We studied 64 adult patients undergoing elective haemorrhoidectomy. Caudal block was performed in all patients using a mixture of 0.5% bupivacaine 35 mg with 2% lidocaine 140 mg and epinephrine 5 micrograms ml-1. Patients were allocated randomly to one of two groups. Clonidine 75 micrograms was added in group C and saline 1 ml in group S. Median time to first analgesic requirements was significantly longer in group C (mean 729 (SD 120) min) than in group S (276 (131) min) (P = 0.01). Bradycardia occurred in seven patients in group C but did not affect mean arterial pressure. (+info)
Contemporary activation of different endothelial receptors accounts for a reserve mechanism of nitric oxide-mediated relaxation.
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The aim of this study was to investigate whether the inhibition of one of the endothelial receptor sites in the rat pulmonary artery (muscarinic, histaminergic, purinergic, alpha2-adrenergic) affects the NO-mediated relaxation induced by the activation of the other type of receptors. Acetylcholine (ACh)-, histamine (Hist)-, adenosine (Ade)-, and clonidine (Clon)-induced endothelium-dependent relaxations were reduced by the administration of specific antagonists of muscarinic, H1-histaminergic, purinergic or alpha2-adrenergic receptors, respectively. The inhibition of H1-histaminergic receptors by chlorphenyramine did not prevent ACh-induced relaxation. Similarly, the inhibition of muscarinic receptors by atropine did not prevent the relaxations to histamine, adenosine and clonidine. On the other hand, the relaxations induced by acetylcholine, histamine, adenosine or clonidine were regularly reduced by NO-synthase inhibitor N(G)-nitro-L-arginine methyl ester (10(-4) mol/l). These results suggest that the inhibition of NO-synthase abolished arterial relaxations induced by all agonists. After inhibition of one type of the endothelial receptors, the NO-dependent relaxation could still be evoked by activation of one of the others. (+info)
Control of epithelial Cl(-) secretion by basolateral osmolality in the euryhaline teleost Fundulus heteroclitus.
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Euryhaline teleost fish adapt rapidly to salinity change and reduce their rate of ion secretion on entry to fresh water. Killifish (Fundulus heteroclitus) transferred from full-strength sea water to fresh water showed large reductions in plasma [Na(+)] and osmolality at 6 h which were corrected by 24 h. To mimic this in vitro, a hypotonic shock of 20-70 mosmol kg(-)(1) was applied on the basolateral side of opercular epithelia. This hypotonic shock reversibly reduced the short-circuit current (I(sc), equivalent to the rate of secretion of Cl(-)) in a dose-dependent fashion, with a 40 mosmol kg(-)(1) hypotonic shock reducing I(sc) by 58+/-4.6 % in 40 min. Similar reductions in [NaCl], but with added mannitol to maintain osmolality, were without effect, indicating that the effect was purely osmotic. Hypotonic inhibition of I(sc) was accompanied by reductions in epithelial conductance (G(t)) but no significant change in transepithelial potential (V(t)). The hypotonic inhibition was apparently not Ca(2+)-mediated because Ca(2+)-depleted salines, thapsigargin and ionomycin all failed to block the reduction in I(sc) produced by hypotonic shock. The inhibition was not mediated via a reduction in intracellular cyclic AMP level because cyclic AMP levels, measured by radioimmunoassay, were unchanged by hypotonic shock and by 1.0 micromol l(-)(1) clonidine (which inhibits I(sc) by changing intracellular [Ca(2+)]) but were increased markedly by 1.0 micromol l(-)(1) isoproterenol, a positive control. The protein tyrosine kinase inhibitor genistein (100 micromol l(-)(1)), but not its inactive analogue daidzein, inhibited I(sc) in normal osmolality but produced a stimulation of I(sc) after hypotonic shock (and after clonidine treatment). The inhibitory effects of genistein and hypotonicity were not additive, suggesting that the same portion of the I(sc) was inhibited by both treatments. These data are consistent with a model for Cl(-) transport regulation involving tyrosine phosphorylation in cell-swelling-induced inhibition of Cl(-) secretion when euryhaline teleosts adapt to fresh water. (+info)
Coupling of I(1) imidazoline receptors to the cAMP pathway: studies with a highly selective ligand, benazoline.
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Clonidine and benazoline are two structurally related imidazolines. Whereas clonidine binds both to alpha(2)-adrenoceptors (alpha(2)R) and to I(1) imidazoline receptors (I(1)R), benazoline showed a high selectivity for imidazoline receptors. Although the alpha(2)R are negatively coupled to adenylate cyclase, no effect on cAMP level by activation of I(1)R has been reported so far. We therefore aimed to compare the effects of clonidine and benazoline on forskolin-stimulated cAMP levels in cell lines expressing either I(1)R only (PC12 cells), alpha(2)R only (HT29 cells), or I(1)R and alpha(2)R together (NG10815 cells). Clonidine proved able to decrease the forskolin-stimulated cAMP level in the cells expressing alpha(2)R and this effect could be blocked by rauwolscine. In contrast, in cells lacking these adrenoceptors, clonidine had no effect. On the other hand, benazoline and other I(1) receptor-selective imidazolines decreased forskolin-stimulated cAMP level in the cells expressing I(1)R, in a rauwolscine- and pertussis toxin-insensitive manner. These effects were antagonized by clonidine. According to these results, we demonstrated that 1) alpha(2)R and I(1)R are definitely different entities because they are expressed independently in different cell lines; 2) alpha(2)R and I(1)R are both implicated in the cAMP pathway in cells (one is sensitive to pertussis toxin and the other is not); and 3) I(1)R might be coupled to more then one transduction pathway. These new data will be essential to further understand the physiological implications of the I(1)R and the functional interactions between I(1) receptors and alpha(2)-adrenoceptors. (+info)
Topography of clonidine-induced electroencephalographic changes evaluated by principal component analysis.
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BACKGROUND: Principal component analysis is a multivariate statistical technique to facilitate the evaluation of complex data dimensions. In this study, principle component analysis was used to reduce the large number of variables from multichannel electroencephalographic recordings to a few components describing changes of spatial brain electric activity after intravenous clonidine. METHODS: Seven healthy volunteers (age, 26 +/- 3 [SD] yr) were included in a double-blind crossover study with intravenous clonidine (1.5 and 3.0 microg/kg). A spontaneous electroencephalogram was recorded by 26 leads and quantified by standard fast Fourier transformation in the delta, theta, alpha, and beta bands. Principle component analysis derived from a correlation matrix calculated between all electroencephalographic leads (26 x 26 leads) separately within each classic frequency band. The basic application level of principle component analysis resulted in components representing clusters of electrodes positions that were differently affected by clonidine. Subjective criteria of drowsiness and anxiety were rated by visual analog scales. RESULTS: Topography of clonidine-induced electroencephalographic changes could be attributed to two independent spatial components in each classic frequency band, explaining at least 85% of total variance. The most prominent effects of clonidine were increases in the delta band over centroparietooiccipital areas and decreases in the alpha band over parietooccipital regions. Clonidine administration resulted in subjective drowsiness. CONCLUSIONS: Data from the current study supported the fact that spatial principle component analysis is a useful multivariate statistical procedure to evaluate significant signal changes from multichannel electroencephalographic recordings and to describe the topography of the effects. The clonidine-related changes seen here were most probably results of its sedative effects. (+info)
The mechanical antihyperalgesic effect of intrathecally administered MPV-2426, a novel alpha2 -adrenoceptor agonist, in a rat model of postoperative pain.
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BACKGROUND: MPV-2426 is a novel alpha2-adrenoceptor agonist developed for spinal pain therapy. It has proved to be effective in physiologic and neuropathic conditions. In the current study its effectiveness on mechanical hyperalgesia was assessed in a rat model of postoperative pain. METHODS: Rats with intrathecal catheters were anesthetized with pentobarbital, and a 1-cm incision was made in the plantar aspect of the foot and closed. During postoperative days 1 and 2 the antihyperalgesic effects induced by intrathecal MPV-2426, clonidine, and dexmedetomidine were determined by assessing the hind limb withdrawal threshold to calibrated von Frey hairs applied to the skin of the hind paw adjacent to the wound. RESULTS: MPV-2426 administered into the lumbar spinal cord produced a dose-dependent (0.3-10 microg) attenuation of the mechanical hyperalgesia, and this antihyperalgesic effect was completely reversed by yohimbine (1 mg/kg, subcutaneous), an alpha2-adrenoceptor antagonist. Dexmedetomidine (1-3 microg) produced an equipotent antihyperalgesic effect, whereas the effect of clonidine (1-10 microg) was markedly weaker. MPV-2426 (10 microg in 20 microl) administered adjacent to the wound did not produce any effect. Preoperative treatment with an antihyperalgesic dose of MPV-2426 did not prevent the development of hyperalgesia. CONCLUSIONS: Intrathecal MPV-2426 dose-dependently attenuates postoperative hyperalgesia to mechanical stimulation because of an action on alpha2 adrenoceptors. Its antihyperalgesic action is as effective as that produced by dexmedetomidine and is considerably stronger than that produced by clonidine. However, preoperative treatment with MPV-2426 does not prevent the development of postoperative hyperalgesia. (+info)
Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function.
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RATIONALE: Visceral sensation and motility are important in functional gut disorders and are partly controlled by adrenergic innervation. OBJECTIVES: To characterize the alpha2-adrenergic control of motor and sensory function of descending colon and rectum. METHODS: In 32 healthy volunteers, we assessed compliance, fasting and postprandial tone, and sensations of gas, urgency and pain during phasic distentions. Each subject received one agent at clinically approved doses: clonidine (0.05, 0.1, 0.2 or 0.3 mg p.o. ); or the alpha2 antagonist yohimbine (0.0125 mg, 0.05 mg, 0.125 mg or 0.2 mg intravenously and infusion over 2.5 h). RESULTS: Clonidine increased colonic and rectal compliance, and reduced tone, pain, gas sensation and rectal urgency. Clonidine showed large pairwise differences in sensation and motility between 0.05 and 0.1 mg doses, which did not interfere with the colon's motor response to feeding. Conversely, yohimbine dose-dependently altered the compliance curve, increased tone and sensations of gas, pain and urgency. Drug effects in the colon were more marked at low distensions; alpha2 modulation of rectal sensation was observed at all levels of distension. CONCLUSIONS: alpha2-adrenergic mechanisms modulate colorectal sensations and motility; at doses as low as 0.05 mg, clonidine reduced colorectal sensation while the tone response to feeding was preserved. These studies provide insight into the potential use of alpha2 agents in disease states. (+info)
Norepinephrine release from spinal synaptosomes: auto-alpha2 -adrenergic receptor modulation.
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BACKGROUND: Clonidine produces analgesia after spinal injection by activating alpha2-adrenergic receptors. Recently, clonidine has been demonstrated to increase spinal release of norepinephrine (NE) in vivo, in contrast to that anticipated by classic presynaptic autoinhibition. The purpose of the current study was to determine if clonidine could inhibit release of NE in a preparation of spinal cord tissue lacking synaptic circuits. METHODS: Crude synaptosomes were prepared from male Sprague-Dawley rat spinal cord, loaded with [3H]NE, and stimulated by potassium chloride to release [3H]NE. Samples were incubated with clonidine in the absence or presence of various inhibitors. To study the effect of alpha2a-adrenergic receptor subtypes, some animals were pretreated with an oligodeoxynucleotide (ODN) composed of a sense or antisense sequence to a portion of this receptor. RESULTS: Potassium chloride produced a concentration-dependent increase in [3H]NE release, and this release was inhibited by clonidine with a concentration producing 50% maximal inhibition (IC50) of 1.3 microm. The effect of clonidine was inhibited by the alpha2-adrenergic antagonists, yohimbine and idazoxan, but not by alpha1-adrenergic, muscarinic, or opioid antagonists. Intrathecal pretreatment with antisense ODN to alpha2A-adrenergic receptors reduced alpha2A-adrenergic receptor protein expression compared with sense ODN control and also reduced clonidine-induced inhibition of [3H]NE release. CONCLUSIONS: These data demonstrate the existence of classic autoinhibitory alpha2-adrenergic receptors in the spinal cord, probably of the alpha2Asubtype. They further suggest that clonidine-induced stimulation of spinal NE release must occur from indirect actions, presumably due to activation of a spinal circuit. (+info)