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1.
α2-adrenoceptor agonist drugs can cause respiratory changes leading to a short period of hypoxaemia in sheep. It has been suggested that this is due to transient platelet aggregation and pulmonary microembolism. If platelet aggregation were to follow platelet activation in response to the administration of α2 agonists, plasma thromboxane levels would be expected to rise. This study was carried out to measure plasma thromboxane B2 concentrations before and after the intravenous administration of the α2-agonist drug xylazine at a dose of 0.1 mg/kg. It was found that the plasma thromboxane concentration rose by 320% and, furthermore, the rise was prevented by the prior administration of atipamezole hydrochloride (0.125 mg/kg), an α2-adrenoceptor antagonist.  相似文献   

2.
Medetomidine, an α2-adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 μg kg-1) was followed by a dose of atipamezole (250 μg kg-1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC-MS. Statistical analysis of the results (anova) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml"1(P = 0.005), t1/4 from 1.44 to 0.87 h ( P = 0.015), and increased Cl from 21 to 31 ml min-1kg-1(P = 0.017). Differences in V2 did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and C max as well as the increase of AUC . It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.  相似文献   

3.
Rings of equine digital vein examined under conditions of isometric tension recording constricted to alpha-adrenoceptor agonists with an order of potency of 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline bitartrate (UK 14304) = noradrenaline > 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine (BHT-920) > phenylephrine > dopamine > methoxamine. The maximum force generated was greatest for the non-selective agonist noradrenaline and lowest for the alpha2-selective agonist BHT-920 with the other agonists between these two extremes. Selective inactivation of alpha1-adrenoceptors (achieved by treating yohimbine-protected tissues with phenoxybenzamine) reduced the maximum responses of all agonists, the EC50 values of UK 14304, BHT-920 and noradrenaline and increased the EC50 values of phenylephrine and methoxamine. Prazosin (30 n M ) had no inhibitory effect on responses to low concentrations of BHT-920 and UK 14304 and caused competitive inhibition of responses to phenylephrine and noradrenaline giving pKb values of 8.49 ± 0.18 and 8.23 ± 0.14, respectively. Yohimbine (0.1 μ M ) caused significant competitive inhibition of responses to BHT-920 and noradrenaline with calculated pKb values of 8.43 ± 0.11 for BHT-920 and 7.43 ± 0.31 for noradrenaline and non-competitive inhibition of responses to UK 14304. 2-[2-methoxy-1,4-benzodioxan-2-yl]-2-imidazoline (RX 821002; 10 n M ) caused competitive inhibition of responses to BHT-920 (pKb 9.04 ± 0.27) and dopamine (pKb 8.2 ± 0.2). These data indicate that equine digital veins possess both post-synaptic alpha1 and alpha2-adrenoceptors.  相似文献   

4.
The pharmacokinetics of medetomidine hydrochloride (Domitor) administered at a single dose of 15 μg/kg IV in sheep are described. Plasma medetomidine concentrations were determined using a sensitive radioreceptor assay technique, capable of also measuring metabolites which would bind to α2 adrenergic receptors. Medetomidine was rapidly distributed, with a half-life of distribution of 4.65/pm0.65 min. The apparent volume of distribution was 2.69/pm0.62 L/kg, while elimination half-life was 37.85/pm2.84 min. Total body clearance varied between 16.29 and 151.81 mL/min.kg. Pharmacological effects of medetomidine paralleled its plasma concentration.  相似文献   

5.
The effect of medetomidine, a potent and highly selective α2-adrenoceptor agonist, on the motility of the gastric antrum, duodenum, mid-jejunum and ileum was investigated in ten dogs. Its effect on the release of gastrin was also determined. Administration of medetomidine intramuscularly (i.m.) at a dose of 40 μg/kg inhibited the motility of the gastric antrum, duodenum, mid-jejunum and ileum significantly, in comparison to administration of xylazine intramuscularly at a dose of 2.0 mg/kg. The release of gastrin was also significantly decreased in dogs receiving medetomidine. It was found to inhibit the motility in the gastric antrum and duodenum longer than in the mid-jejunum and ileum, presumably by acting specifically on α2-adrenoceptors, likely at the peripheral level. Medetomidine also inhibited the gastric contraction associated with gastrin secretion.  相似文献   

6.
A radioreceptor assay technique is described for the measurement of xylazine and medetomidine in sheep plasma. The assay was based on the displacement of tritiated clonidine from a 2-adrenoceptors in a rat brain homogenate by xylazine or medetomidine extracted from plasma. Plasma samples from sheep which had been given xylazine and medetomidine were treated with alumina to remove endogenous catecholamines which would otherwise have bound to α2-- adrenoceptors and interfered with the assay. The drugs were then extracted using chloroform, reconstituted in buffer and used to displace [3H]clonidine. The concentration of α2-agonist was calculated by reference to standard curves. The method had a detection limit of 2.5 ng/mL for xylazine and 0.24 ng/mL for medetomidine. The assay could also be used to detect metabolites capable of binding to α2-receptors.  相似文献   

7.
α2-Adrenergic receptor agonists are widely used in veterinary medicine as sedative/hypnotic agents. Four pharmacological subtypes of the α2-adrenergic receptor (A, B, C and D) have been identified based primarily on differences in affinity for several drugs. The purpose of this study was to examine the affinities of the sedative agents, xylazine, detomidine and medetomidine at the four α2-adrenergic receptor subtypes. Saturation and inhibition binding curves were performed in membranes of tissues containing only one subtype of a2-adrenergic receptor. The KD for the α2-adrenergic receptor radioligand, [3H]-MK-912, in HT29 cells (α2A-), neonatal rat lung (α2B-), OK cells (α2C-) and PC12 cells transfected with RG20 (α2D-) were 0.38 ± 0.08 n m , 0.70 ± 0.5 n m , 0.07 ± 0.02 n m and 0.87 ± 0.03 n m , respectively. Detomidine and medetomidine had approximately a 100 fold higher affinity for all the α2-adrenergic receptors compared to xylazine but neither agonist displayed selectivity for the α2-adrenergic receptor subtypes. These data suggest that available sedative/hypnotic α2-adrenergic receptor agonists can not discriminate between the four known α2-adrenergic receptor subtypes.  相似文献   

8.
The effect of xylazine on the isolated sheep trachea and its possible interactions with the α2-adrenergic antagonist, atipamezole, and the anticholinergic agent, atropine, was studied. The mechanical responses of the tracheal preparations were recorded after exposing each one to cumulatively increasing concentrations of xylazine alone or in the presence of atipamezole or atropine.
Xylazine exerted a concentration-dependent contractile effect, with a threshold concentration of 10--7M while the maximum activity was produced at a concentration of 10--5M (EC50= 2.3 × 10--7). This xylazine-induced contractile effect was inhibited by atipamezole, but not significantly modified by atropine. Thus, it is concluded that α2-adrenoceptors exist in the sheep trachea and it is suggested that α2-adrenoceptor agonists may act on airways in sheep directly through stimulation of peripheral α2-adrenergic receptors and indirectly via central α2-adrenergic receptor activation of parasympathetic tone.  相似文献   

9.
Strips of tracheal smooth muscle from 12 horses were contracted by carbachol in tissue baths under isometric conditions. This contraction (≅50% of maximum: EC50) was relaxed completely with adrenoceptor drugs. The only exception was clenbuterol, where the degree of relaxation was ≅90%. In all horses the EC50-value for isoprenaline (mean 1.6 × 10−8M) was less than that for adrenaline (mean 9.6 × 10− 8M) and noradrenaline (mean 1. 8 × 10- 6M). The potency ratio was 1 < 6 < 110 which indicates that the β2-subtype dominates among the β-adrenoceptors of equine airways. All preparations were also very sensitive to the specific and potent β2-receptor agonists clenbuterol (mean 5.7 × 10− 9M) and procaterol (mean 3.6 × 10−10M). No differences in EC50-values due to age, sex and breed were observed in this material. The standard deviation of the mean EC50-values seems to be larger for the specific β2-adrenoceptor agonists than for the unspecific. A reason for this could be differences in the pattern of the β-adrenoceptor population.  相似文献   

10.
The pharmacokinetics of two potent α2-adrenoceptor agents that can be used for immobilization (medetomidine) and reversal (atipamezole) of the sedation in mammals, were studied in three reindeer ( Rangifer tarandus tarandus) in winter and again in summer. Medetomidine (60 μg/kg) was injected intravenously (i.v.), followed by atipamezole (300 μg/kg) intravenously 60 min later. Drug concentrations in plasma were measured by HPLC. The administration of atipamezole resulted in an immediate 2.5–3.5 fold increase in the medetomidine concentration in plasma. Clearance for medetomidine (median 19.3 mL/min·kg) was lower than clearance for atipamezole (median 31.0 mL/min·kg). The median elimination half-lives of medetomidine and atipamezole in plasma were 76.1 and 59.9 min, respectively. The animals became resedated 0.5–1 h after the reversal with atipamezole. Resedation may be explained by the longer elimination half-life of medetomidine compared to atipamezole.  相似文献   

11.
Medetomidine is an α2-adrenoceptor agonist with sedative and analgesic properties. Previously we demonstrated significant differences in the response to medetomidine between two inbred rabbit strains, denoted IIIVO/JU and AX/JU. The aim of the present study was twofold: first, to compare the hepatic CYP450 enzyme activities between these rabbit strains [ n  = 13(6♂♂,7♀♀)/strain]. To this end, liver microsomes were incubated with known fluorescent substrates for the major drug-metabolizing CYP450 isoforms. A comparison of the obtained results indicated significant gender differences as well as differences between the two rabbit inbred strains. Secondly, the biotransformation rate of medetomidine in liver microsomes of both rabbit strains was determined using liquid chromatography coupled to tandem mass spectrometry. The rate of hydroxymedetomidine and medetomidine carboxylic acid formation was found to be significantly higher in the AX/JU strain. Specific CYP2D and CYP2E inhibitors could decrease the formation of both metabolites. Significant correlations were found between the rate of biotransformation of medetomidine and the activities of CYP2D and CYP2E, as well as between CYP450 enzyme activities and the anaesthetic response to medetomidine.  相似文献   

12.
We investigated the effect of bradykinin (BK) on isolated equine basilar arterial rings with and without endothelium. BK induced concentration-dependent contraction of resting arterial rings and no relaxation when the rings were precontracted by prostaglandin F2α. The maximal response and pD2 value were 161.2 ± 28.1% (to 60 m m KCl-induced contraction) and 8.24 ± 0.25 respectively. The cumulative concentration–response curve for BK was not shifted to the right by des-Arg9-[Leu8]-BK (a B1-receptor antagonist), HOE140 (a B2-receptor antagonist) or NPC567 (another B2-receptor antagonist). In four of six basilar arteries, NPC567 induced concentration-dependent contraction. Indomethacin (a cyclooxygenase inhibitor), nordihydroguaiaretic acid (a lipoxygenase inhibitor), quinacrine (a phospholipase A2 inhibitor), tetrodotoxin (a selective blocker of Na+ channels), guanethidine (a nor-adrenergic neuron blocking drug), phentolamine (an α-adrenoceptor antagonist), Nω-nitro- l -arginine ( l -NNA, a nitric oxide (NO) synthase inhibitor) and endothelial denudation did not affect the BK-induced contraction. l -NNA and indomethacin induced contraction and relaxation under resting vascular tone respectively. These results suggest that endothelial cells are not involved in BK-induced contraction and that the contraction is not mediated via activation of known B1 and B2 receptors. Arachidonic acid metabolites and neurotransmitters like norepinephrine and NO might not play a role in BK-induced contraction in equine basilar artery.  相似文献   

13.
Acute pharmacodynamic effects of the α2-adrenoceptor agonists, xylazine and guanfacine, were investigated in nine healthy calves in an open crossover trial. Xylazine (100 μg/kg body weight intravenously (i.v.)) and guanfacine (20 μg/kg body weight i.v.) were equi-effective in lowering heart rate by 25–30% at 5 min. Under these conditions, xylazine induced strong sedation and increased plasma growth hormone levels, indicating central nervous system mediated actions, whereas guanfacine was not sedative and did not induce release of growth hormone. Oxygen consumption was decreased by both drugs, but respiratory exchange ratio decreased only in response to xylazine. However, in response to both drugs, plasma levels of noradrenaline, adrenaline, insulin and non esterified fatty acids decreased similarly and glucose increased comparably. These results demonstrate marked differences in the central nervous system-mediated effects of the two α2-adrenoceptor agonists, whereas peripheral actions are similar.  相似文献   

14.
A critical period of early gestation in the mare involves the immobilization (fixation) of the encapsulated conceptus at around days 16–17. We compared the major proteins in the normal equine embryonic capsule and endometrial secretions around the period of fixation with those from pregnancies in the process of termination induced by administration of an analogue of prostaglandin F2α (PGF2α). Uterocalin and β2-microglobulin (β2M) associated with the embryonic capsule were proteolytically converted to smaller forms during the fixation period. These conversions were similar in conceptuses from control and treated mares. A 17 kDa cationic protein identified as a secretory phospholipase A2 (sPLA2) type IIA was detected bound to normal capsules but increased substantially in response to PGF2α. Two forms of uteroglobin were distinguished by partial amino acid sequences of ∼6 kDa bands in flush fluids from normal pregnant uteri. After administration of PGF2α one immunoreactive form of uteroglobin was preferentially increased. These studies demonstrate that failure of pregnancy in this model is associated with an increase in secretory phospholipase in the capsule and a change in the forms of uteroglobin in the uterine secretions.  相似文献   

15.
Methadone hydrochloride is a synthetic μ-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance ( Cl / F ), small volume of distribution (Vd/ F ) and short elimination half-life ( t 1/2). The mean of the estimated t 1/2 (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated C max (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively.  相似文献   

16.
Effects of medetomidine on intestinal and colonic motility in the dog   总被引：1，自引：0，他引：1  
The motor responses of the jejunum and colon to stimulation of α2-adrenoceptors by medetomidine and clonidine were investigated in four dogs. In fasting dogs, medetomidine, at a dose rate of 30 μg/kg i.v., disrupted the migrating myoelectric complex (MMC) pattern of the small intestine for about 2 h. Similar, but shorter-lasting effects were also induced by clonidine (30 μg/kg i.v.) on the jejunum. The administration of α2-agonists inhibited colonic motility in fasting dogs, although medetomidine-induced inhibition was preceded by a short period of increased muscle tone. All these effects were reversed by the α2-antagonists atipamezole (0.15 mg/kg i.v.) and yohimbine (0.20 mg/kg i.v.). In fed dogs, medetomidine (30 μg/kg i.v.) induced a strong increase of the tone on the proximal colon, while the activity of the medium and distal colon was completely suppressed. Yohimbine (0.50 mg/kg i.v.) immediately restored the activity of the colon and induced a propagated giant contraction and defaecation by the animal. These data confirm the importance of a2-adrenergic receptors in the control of intestinal and colonic motility in the dog.  相似文献   

17.
The cardiopulmonary effects of the intravenous administration of clonidine (15 μg/kg), ST-91 (30 μg/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of α2 adrenoceptor agonists are due to sedation, or to peripheral α2 adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO2) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO2 levels of ≈40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO2 was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO2) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of α2 adrenoceptor agonists in sheep are mainly mediated by peripheral α2 adrenoceptors.  相似文献   

18.
Isolated equine coronary arteries responded to 5-hydroxytryptamine (5-HT) with relaxations in both endothelium-dependent and endothelium-independent mechanisms. Experiments were designed to characterize the 5-HT receptor sub type mediating these relaxations. Both 5-HT and alpha-methyl-5-HT (α-Me-5- HT; 5-HT2 agonist) produced concentration-dependent relaxations in equine coronary arteries precontracted with a thromboxane A2 derivative (0N011113). The degree of the maximal relaxation induced by α t-Me-5-HT was about one-half of that induced by 5-HT. In the coronary arteries without endothelium, α -Me-5-HT produced no relaxation, but 5-HT caused relaxation, which was inhibited by a 5-HT1 antagonist (methysergide, mianserin and methiothepin), but was inhibited neither by ketanserin (5-HT2 antagonist) nor by MDL72222 (5-HT3 antagonist). In the coronary arteries with endothelium, however, the relaxation induced by α -Me-5-HT was inhibited by ketanserin, L-nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor). These results suggest that the relaxation induced by 5-HT in equine coronary arteries depends mainly on the stimulation of both 5-HTi receptor subtype on smooth muscle cells directly, and 5-HT2 receptor subtype on endothelial cells indirectly by liberating endothe-lium-derived NO.  相似文献   

19.
We examined the functional role of adrenergic receptor subtypes (ARs) in bovine intra-mammary arteries (IMAs), 1.5–2.5 mm internal diameter. Norepinephrine (NE) and phenylephrine (PE) produced concentration-dependent increases in tone in segments maintained at a previously determined optimal basal tension in vitro . The sensitivity of the tissue to NE and PE, based on -log molar ED50s was 6.87 ± 0.17 and 7.05 ± 0.35, respectively. In addition a Schild analysis yielded antagonist affinities for the receptor mediating contractile responses to NE (pA2 value) of 10.46 ± 0.85 for prazosin and 6.29 ± 0.18 for yohimbine. These data indicate a dominance of functional alpha 1 (α1) over alpha 2 (α2)-ARs in this tissue. Based on the inhibitory effects of chloroethylclonidine (CEC) on PE responses and the further reduction in sensitivity when nifedipine was added to the CEC, also in the presence of PE, we conclude that there is more than one α1-AR subtype, with a predominant role for α1B-ARs in phenylephrine responses. Stimulation of beta (β)-ARs, resulted in relatively small reductions in tone (the highest magnitude of response was 25.94 ± 6.46% of the papaverine maximum at 3×10−6 M isoproterenol); in addition, propranolol did not significantly alter tissue sensitivity to NE. Additional characterization of functional autonomic receptor populations in this circulatory bed will form a basis for future studies on circulatory dynamics in the mammary gland.  相似文献   

20.
Prostaglandin F2α receptors (PGF2α Rs) were measured in bovine corpus luteum and myometrial cell membranes using a radiometric method. The inhibition of labelled PGF2α binding exerted by d-cloprostenol, dl-cloprostenol, PGF2α and PGE1 (l0–11 M to 10–4 M) was evaluated in vitro. Results strongly suggest that cloprostenol binding to PGF2αRs is stereospecific. d-Cloprostenol and PGF2α were equipotent, about 150 times more potent than d-cloprostenol (P < 0.05) and approximately 280 times more potent than PGE, (P < 0.05) in inhibiting [3H]PGF2α binding to corpus luteum cell membranes. Such differences were less evident in myometrial cell membranes, where d-cloprostenol and PGF2α were about 10 times more potent than d-cloprostenol (P < 0.05) and approximately 95 times more potent than PGEl (P < 0.05).  相似文献   

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