Cardiovascular effects of medetomidine-ketamine anaesthesia in sheep, with and without 100% oxygen, and its reversal with atipamezole.

The cardiovascular effects of intravenously (iv) administered medetomidine 20 μg/kg bodyweight (bwt) and ketamine (2 mg/kgbwt), with and without 100% inspired oxygen, were investigated in six domestic sheep. A second dose of medetomidine and ketamine was administered iv, at dose 10 μg/kg bwt and 1 mg/kg bwt respectively, 25 minutes after the initial injection. Heart rate, PaO₂ pH and haemoglobin saturation decreased whereas PaCO₂ and base excess increased post-injection. Transient hypertension and an increase in respiration rate were evident within the first 10 minutes of anaesthesia. Significant hypoxaemia (P<0.01) developed in sheep breathing room air. Inspired 100% oxygen improved PaO₂ (but the difference was not significant), and improved haemoglobin saturation significantly (P<0.05), however, this effect varied between individuals. One sheep breathing room air suffered a cardiac arrest immediately post-injection and had to be resuscitated. Atipamezole 125 μg/kg given intramuscularly 45 minutes after the initial injection rapidly reversed the effects of medetomidine. Recovery times did not significantly differ although time to extubation and standing tended to be longer in sheep breathing room air compared to the sheep breathing 100% oxygen. The quality of the recovery did not differ.     

The antinociceptive activity and respiratory effects of fentanyl in sheep

The analgesic activity of fentanyl was measured in sheep using both thermal and mechanical test systems. Fentanyl at a dose rate of 5 μg/kg given intravenously (iv) produced significant analgesia to thermal pain for some 30 mins but no detectable mechanical antinociceptive activity. However, at a dose rate of 10 μg/kg the drug produced both thermal (for 60 mins) and mechanical (40 mins) antinociceptive effects. In one sheep a dose of 20 μg/kg produced thermal analgesia for 110 mins and mechanical antinociception for 60 mins. Following iv injection at 10 μg/kg in five of the sheep, there was a brief period of respiratory depression evidenced by a significant fall in PaCO₂ of the order of 25 per cent and an increase in PCO₂ levels, but these changes were short lived and levels were back to normal at 15 mins after injection.     

The comparative hypoxaemic effect of four α2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep

In the present study, the hypoxaemic potential of four α₂ agonists possessing different selectivity for α₂ adrenoceptors and of a saline placebo was studied in five clinically healthy sheep using a randomized Latin square design and equipotent sedative doses. Baseline values for heart rate (HR), mean arterial pressure (MAP), arterial oxygen (PaO₂) and carbon dioxide (PaCO₂) tensions, respiration rate and maximum change in pleural pressure (ΔPpl) were obtained, followed by the intravenous administration of either: xylazine (150 μg/kg); romifidine (50 μg/kg); detomidine (30 μg/kg); medetomidine (10 μg/kg) or placebo. Subsequent recordings were made up to 60 min after drug administration. No significant (P 0.05) alterations in any variable occurred with placebo. All the α₂ agonists significantly (P 0.05) decreased PaO₂ levels without a significant (P 0.05) change in PaCO₂. The lowest PaO₂ values were 29–42 mm Hg (3.9–5.5 kPa) with no significant difference between drugs. Respiratory rate and ΔPpl increased significantly within 2 min of drug administration; the duration of this effect varied with the α₂ agonist, lasting longest with romifidine. As compared to the saline treated group, a significant increase in MAP was observed up to 10 min after administration of romifidine and detomidine, however, a significant decrease was seen at 10 and 45 min after xylazine and medetomidine, respectively. The α₂ agonists studied induced a similar change in PaO₂ at peak effect, despite their reported variable selectivity for α₂ vs. α₁ adrenoceptors.     

Types of serotonergic receptors involved in the control of reticulo-ruminal myoelectric activity in sheep

The effects of peripheral (intravenous, i.v.) and central (intracerebroventricular, ICV) administrations of agonists of 5-HT_1A, 5-HT₂, 5-HT₃ and 5-HT₄ receptors were investigated in conscious sheep chronically fitted with intraparietal electrodes on the reticulum and the dorsal, ventral and caudo-ventral rumen. The 5-HT_1A agonist 8-hydroxydipropylaminotetralin increased reticular and decreased ruminal spike burst frequency when given i.v. (80 μg/kg) and ICV (8 μg/kg). The 5-HT₂ and 5-HT₃ agonists, α-methylserotonin and 2-methylserotonin, induced a moderate inhibition of rumino-reticular contractions when given i.v. at 100 and 150 μg/kg, respectively, while marked inhibition was observed after ICV administration at doses of 10 and 5 μg/kg, respectively. The 5-HT₄ agonist 5-methoxytryptamine strongly stimulated rumino-reticular motility by the ICV (10 μg/kg) route, whereas it induced a moderate inhibition when administered i.v. (200 μg/kg). The selective antagonist of 5-HT_1A, 5-HT₂, 5-HT₃ and 5-HT₄ receptors, spiroxatrine, ritanserin, granisetron and DAU 6285, respectively, blocked the responses of the respective agonists given by the same route. Moreover, the antagonists given ICV blocked the effects of the agonists given i.v. except for DAU 6285 ICV, which did not antagonize the inhibition induced by 5-methoxytryptamine i.v. It is concluded that the four types of serotonergic receptors investigated control rumino-reticular motility at the central level. However, according to the receptor type and the forestomach area (reticulum or rumen) this control may be stimulatory or inhibitory, demonstrating a pleiotropic role of serotonin in the control of rumino-reticular motility in sheep.     

Clinical observations on medetomidine/ketamine anaesthesia in sheep and its reversal by atipamezole

Medetomidine (25 μg/kg) and ketamine (1mg/kg) were administered intramuscularly to anaesthetise 13 sheep for experimental oral surgery. Anaesthesia was characterised by good muscle relaxation and tachypnoea. Heart rates were not significantly different from those recorded before administration of the anaesthetic agents. Spontaneous recovery from anaesthesia was allowed in five sheep. In eight sheep atipamezole, at a total dose of 125 μg/kg, divided and administered both intravenously and intramuscularly, hastened return to full awareness.     

Probable post-synaptic α2 adrenergic mediated effect of xylazine on goat uterine motility*

Perez, R., Cox, J.F., Arrue, R. Probable post-synaptic ot2 adrenergic mediated effect of xylazine on goat uterine motility. J. vet. Pharmacol. Therap. 17 , 59–63. Xylazine has been characterized as a selective α₂-adrenoceptor agonist, which has explained its central nervous system depressant and other pharmacological effects. In order to characterize the effect of xylazine on uterine motility during the oestrus cycle in goats intrauterine pressure changes were recorded in cycling goats using balloon-tipped catheters placed in the uterine horns and connected to pressure transducers and a recorder. The effect of xylazine on myometrial activity was studied by giving increasing doses of the drug (1.0, 10.0, 100.0 or 500.0 m̈g/kg) intravenously (i.v.) to animals either in the follicular or the luteal phase of the cycle. To establish the subtype of a adrenergic receptor mediating the action of xylazine, goats were pretreated with either prazosin (1.0 mg/kg, i.v.) or yohimbine (1.0 m̈g/kg, i.v.). To establish whether the effect of xylazine was pre- or post-synaptic, xylazine (100 mg/kg, i.v.) was administered to goats pretreated with reserpine (0.8 mg/kg, i.p.) to deplete presynaptic catecholamine stores. Xylazine induced a significant and dose-dependent increase on uterine motility in cycling goats, apparently mediated by postsynaptic oc₂-adrenoceptors.     

Medetomidine/ketamine sedation in calves and its reversal with atipamezole

Atipamezole was used to reverse the sedation induced in calves by medetomidine/ketamine. Thirteen claves subjected to umbilical surgery received medetomidine 20 μg/kg bodyweight (bwt) and ketamine 0.5 mg/kg bwt intravenously (iv) from a mixture of the drugs in one syringe. Atipamezole was given at doses of 20 to 60 μg/kg iv and intramuscularly (im) to the calves at the end of the operation. Following the administration of medetomidine and ketamine, PaCO₂ increased whereas pH, PaO₂ and heart rate decreased. Reversing the effects of medetomidine with atipamezole did not cause undesirable effects; recovery was rapid and smooth, most of the animals reached a standing position within 1 to 3 mins after the atipamezole injection.     

The influence of atipamezole on the cardiovascular effects of detomidine in horses

The reversal of the cardiovascular effects of the α₂-adrenoceptor agonist detomidine by the α₂-antagonist atipamezole was studied. Nine horses were given detomidine 20 μg/kg iv. On a separate occasion they were given atipamezole 100 μg/kg iv 15 mins after the detomidine injection. Blood gas tensions were measured and clinical signs of sedation were also observed. Bradycardia and the frequency of heart blocks induced by detomidine were reduced after atipamezole and blood pressure decreased. These reversal effects of atipamezole were of short duration (a few minutes) at the dose level tested. Two of the nine horses exhibited premature depolarisations after administration of detomidine, but not after atipamezole injection. PaO₂ decreased and PaCO₂ increased slightly after detomidine injection, but the arterial pH was within reference values or slightly elevated. Administration of atipamezole did not alter these values. Base excess rose after detomidine, and it decreased more quickly towards the baseline level, when the horses were given detomidine alone. No clinical adverse effects were seen from the administration of atipamezole. Atipamezole may be beneficial, if detomidine-induced bradycardia needs to be reversed in horses.     

Effects of endotoxin,interleukin‐1/3 and prostaglandin injections on fever response in broilers

1. The effect of endotoxin, interleukin‐1β and prostaglandin on fever response was studied in 80 broilers (Hubbard strain). Endotoxin (E. coli, LPS) was injected iv (1.5 μg/kg) and icv (1.5 μg/bird); interleukin‐1 (human recombinant IL‐1β, 80 pg/bird) and prostaglandin E₂ (5 μg/bird) were injected icv. Indomethacin (10 mg/kg, iv) pretreatment was also used before iv endotoxin injection.

2. The results showed that indomethacin was able to block the fever response induced by iv endotoxin injection, and IL‐1β and PGE₂ were both effective in producing fever when injected icv. These data suggest a prostaglandin‐mediated fever response by broilers, and also a strong evidence of the involvement of endogenous pyrogen (interleukin‐1) in fever response in birds.     

A COMPARISON OF THE SEDATIVE EFFECTS OF MEDETOMIDINE AND XYLAZINE IN THE HORSE.

The sedative effects in horses of the new α₂-agonist medetomidine were compared with those of xylazine. Four ponies and one horse were treated on separate occasions with two doses of medetomidine (5 mμ/kg bodyweight and 10 μg/kg bodyweight) and with one dose of xylazine (1 μg/kg bodyweight) given by intravenous injection. Medetomidine at 10 μg/kg was similar to 1 mg/kg xylazine in sedative effect but produced greater and more prolonged ataxia. Ataxia was so severe following 10 μg/kg of medetomidine that one animal fell over during the study. Medetomidine (5 μg/kg) produced less sedation but a similar degree of ataxia to 1 mg/kg xylazine.     

Selectivity of atipamezole, yohimbine and tolazoline for alpha-2 adrenergic receptor subtypes: Implications for clinical reversal of alpha-2 adrenergic receptor mediated sedation in sheep

The α₂-adrenergic receptor antagonists, yohimbine, atipamezole and tolazoline, are used in veterinary medicine as reversal agents for the sedative/hypnotic effects of α₂-agonists. Ruminants have increased sensitivity to the sedative/hypnotic effects of α₂-agonists compared to other species. The receptors mediating the sedative effects of α₂-agonsts are located primarily on locus coeruleus neurons in the pons of the lower brainstem. Four pharmacological subtypes of the α₂-adrenergic receptor (A,B, C and D) have been identified based on differences in ligand affinity. The aim of this study was to: 1) determine the pharmacological profile of atipamezole, yohimbine and tolazoline at the four α₂-adrenergic receptor subtypes and; 2) determine whether these agents differ in their affinities at the α₂-adrenergic receptor present in the sheep brainstem. In inhibition binding studies against the selective α₂-adrenergic receptor ligand [³H]-MK-912, tolazoline showed the lowest affinity for all four α₂-adrenergic receptor subtypes compared to yohimbine and atipamezole. The affinities of yohimbine and atipamezole were similar at the α_2A-, α_2B- and α_2C-adrenergic receptors but differed by approximately 100 fold at the α_2D-adrenergic receptor. Atipamezole had a 100 fold higher affinity at the α_2D-adrenergic receptor when compared to yohimbine. To determine the ligand binding characteristics of these agents at the α₂-adrenergic receptor in sheep brainstem, membranes were labelled with [³H]-MK-912 and inhibition competition curves were performed. Atipamezole showed approximately a 100 fold higher affinity for the sheep brainstem α₂-adrenergic receptor compared to yohimbine which was similar to what was observed for the α_2D-adrenergic receptor in PC12 cells transfected with RG-20. The results from these studies suggest that atipamezole has a high affinity for the α_2D-adrenergic receptor that appears to be the receptor subtype in sheep brainstem.     

Propofol infusion anaesthesia in dogs pre-medicated with medetomidine

Ten laboratory beagles pre-medicated with medetomidine (40 μg/kg bodyweight [bwt]) were anaesthetised using a rapid injection of propofol, followed by propofol infusion. A loading dose of 4 mg/kg bwt of propofol was administered intravenously (iv) as a bolus and, immediately after, a 60 min iv propofol infusion (150 μg/kg bwt/min) was initiated. After a transient increase, mean arterial blood pressure decreased significantly below the pre-propofol level. However, the lowest values recorded (115 ± 11 mmHg) remained within the physiological limits. Heart rate increased significantly (from 41 ± 7.3 to 58 ± 11 beats/min) after initiation of the propofol infusion. No significant changes were seen in respiratory frequency; pO₂ decreased transiently; minimum values (10 ± 2.3 kPa) recorded 5 mins after initiation of the propofol infusion differed significantly from the starting level. pCO₂ increased significantly and the highest values recorded were 6.1 ± 0.35 kPa. Accordingly, pH decreased reaching the lowest level (pH 7.29) 15 mins after initiation of the propofol infusion. The analgesic effect of the present combination was not studied, but the absence of the palpebral and pedal reflexes suggested a surgical stage of anaesthesia. Therefore, propofol infusion in beagles pre-medicated with medetomidine proved to be a promising anaesthetic regimen but, if used clinically, oxygen-enriched inspired air should be used.     

Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the race-mate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+) (S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (C_max 18 μg/ml, AUC_0–24 118 μg h/ml) than the (+)(S) (C_max 14 μg/ml, AUC_0–24 67 μg h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but C_max and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by C_max and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B₂ (T × B2) generation by platelets in clotting blood (serum T × B₂, or prostaglandin E₂, (PGE,) and 12-hydroxyeicosatetraenoic acid (1 2-HETE) synthesis in inflammatory exudate. Since other studies have shown that rac-CPF at the 4 mg/kg dose rate possesses analgesic and anti-inflammatory effects in the dog, it is concluded that the principal mode of action of the drug must be by mechanisms other than cyclooxygenase or 12-lipoxygenase inhibition.     

Fecal alpha1-proteinase inhibitor concentration in dogs receiving long-term nonsteroidal anti-inflammatory drug therapy

Background: Fecal α₁‐proteinase inhibitor (α₁‐PI) clearance is a reliable, noninvasive marker for protein‐losing enteropathy (PLE) in human beings. An assay for measurement of this protein in the dog has been developed and validated and may be useful for the investigation of gastrointestinal disease in this species. Nonsteroidal anti‐inflammatory drugs (NSAIDs) frequently are administered to dogs and may have adverse effects on the gastrointestinal tract, including gastroduodenal ulceration and altered mucosal permeability. The value of fecal α₁‐PI measurement in detecting unrelated gastrointestinal disease may be limited in dogs on NSAID therapy, but α₁‐PI may be a useful marker for NSAID‐induced gastrointestinal damage. Objective: The aim of this study was to evaluate the effects of long‐term administration of NSAIDs on fecal α₁‐PI concentrations in dogs. Methods: Fecal samples were collected from 2 groups of dogs: 1) 21 clinically‐healthy client‐owned dogs without signs of gastrointestinal disease and receiving no NSAIDs and 2) 7 dogs referred for investigation and treatment of orthopedic disorders; the dogs had received either meloxicam or carprofen daily for at least 30 days. Fecal α₁‐PI concentration was measured by ELISA. Results: Fecal α₁‐PI concentrations, expressed as μg/g of feces, were not significantly different between groups 1 and 2 (median [range], group 1: 9.9 μg/g [0.0–32.1 μg/g]; group 2: 5.6 μg/g [1.1–32.3 μg/g]; P= .81). Conclusions: These results suggest that use of cyclooxygenase‐2‐selective NSAIDs, such as carprofen and meloxicam, does not significantly affect fecal α₁‐PI measurements. However, study numbers were small, and larger prospective trials are required to assess more accurately the gastrointestinal effects of NSAIDs in dogs.     

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma,exudate and transudate in sheep

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t_½β) of 2.48 ± 0.12 h and an area under the concentration – time curve (AUC) of 30.61 ± 3.41 μg/mL.h. Elimination of PBZ from plasma was slow (t_½β = 17.92 ± 1.74 h, AUC = 968.04 ± μg/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (C_max) for FM of 1.82 ± 0.22 μg/mL at 5.50 ± 0.73 h (exudate) and 1.58 ± 0.30 μg/mL at 8.00 h (transudate), and C_max for PBZ of 22.32 ± 1.29 μg/mL at 9.50 ± 0.73 h (exudate) and 22.07 ± 1.57 μg/mL at 11.50 ± 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUC_last ratio obtained in the FM and PBZ groups (80–98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.     

Assessment of the sedative effects of buprenorphine administered with 20 microg/kg detomidine in horses

The aim of this randomised, observer-blinded, crossover study was to compare the effects of four treatments, administered intravenously to six horses: saline and saline; 10 μg/kg detomidine and 7.5 μg/kg buprenorphine; 20 μg/kg detomidine and 7.5 μg/kg buprenorphine; and 20 μg/kg detomidine and 10 μg/kg buprenorphine. Sedation was subjectively assessed and recorded on a visual analogue scale. Peak sedation and duration of sedation were investigated using a univariate general linear model with post-hoc Tukey tests (P<0.05). Increasing the dose of detomidine from 10 to 20 μg/kg increased the degree of sedation when administered with the same dose of buprenorphine (7.5 μg/kg). When administered with 20 μg/kg detomidine, increasing the dose of buprenorphine from 7.5 to 10 μg/kg did not influence the degree of sedation achieved.     

Effects of α2-adrenergic drugs on small intestinal motility in the horse: An in vitro study

The effects of selective α₂-agonists (xylazine, detomidine and medetomidine) and antagonists (yohimbine and atipamezole) on in vitro small intestine motility in the horse were evaluated. Samples of equine jejunum were placed in isolated organ baths and drug-induced modifications of motility were measured by means of an isotonic transducer. All tested α₂-agonists dose-dependently reduced both spontaneous and electrically-evoked phasic contractions. Conversely, α₂-antagonists were ineffective when tested alone, and showed a heterogeneous and dose-independent ability to inhibit agonist activity. In particular, the antagonism exerted by higher concentrations of both yohimbine and atipamezole against α₂-agonists was weaker than when lower concentrations were used. The data are indicative of the presence of both pre- and post-synaptic α₂-adrenoceptors with inhibitory activity on equine jejunum motility, and support a possible therapeutic utility of these drugs in horse intestinal disorders associated with hypermotility.     

Effects of dopamine receptor agonists on food intake and rumen motility in dwarf goats

Kaya, F., Van Duin, C.T.M. & Van Miert, A.S.J.P.A.M. Food intake and rumen motility in dwarf goats. Effects of some dopamine receptor agonists. J. vet. PharmacolTherap, 17 , 120–126. In ruminants, the dopaminergic regulation of feeding behaviour has not been investigated. Therefore, the effects of dopamine receptor agonists and antagonists on food intake and forestomach motility were studied in dwarf goats Goats treated i.v. with bromocriptine (1 μg or 2.5 μg/kg body wt/min during 10 min) ate less food than when treated with saline. This inhibitory effect on food intake could not be prevented by the peripheral dopamine receptor antagonist domperidone (0.5 mg/kg body wt i.v.). In contrast, dopamine (i.v. 20 μg/kg body wt/min during 15 min), levodopa (i.v. 40 μg/kg body weight during 10 min), apomorphine (i.v. 2 μg/kg body wt/min during 10 min) and lisuride (i.v. 0.2 μg/kg body wt/min during 15 min and 0.5 μg/kg body wt during 10 min) failed to modify food intake. Given in association with benserazide, a decarboxylase inhibitor (i.v. 20 μg/kg body wt/min during 10 min), levodopa was still inactive as an anorectie agent. Levopoda, bromocriptine and lisuride administered at similar dose rates to those which were used in the food intake experiments, induced some clinical signs including inhibition of forestomach contractions. The inhibition of rumen contractions induced by these drugs was completely antagonized by domperidone pretreatment. These results, together with earlier in vivo and in vitro observations, suggest that the inhibitory effects of dopamine receptor agonists on forestomach contractions are due to interactions with peripheral dopaminergic receptors. The change in smooth muscle tension, which leads to a change in the signals transmitted via vagal afferents to the central nervous system, probably does not modify feeding behaviour in dwarf goats. Furthermore, i.v. infusion of lisuride induced rumination when the inhibition of the forestomach contractions was prevented by domperidone; this effect may involve α₂-adrenoceptor activation.     

The effects of L‐659,066, a peripheral α2‐adrenoceptor antagonist,and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep

Raekallio M. R., Honkavaara J. M., Vainio O. M. The effects of L‐659,066, a peripheral α₂‐adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep. J. vet. Pharmacol. Therap. 33 , 434–438. We investigated whether administration of L‐659,066, a peripheral α₂‐adrenoceptor antagonist, or verapamil, a calcium‐channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross‐over design: dexmedetomidine (5 μg/kg, DEX); DEX with L‐659,066 (250 μg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 ± 10.7 to 120.8 ± 11.7 mmHg), central venous pressure (CVP) (3.3 ± 3.2 to 14.7 ± 5.0 mmHg) and systemic vascular resistance (SVR) (1579 ± 338 to 2301 ± 523 dyne s/cm⁵), and decreases in cardiac output (CO) (5.36 ± 0.87 to 3.93 ± 1.30 L/min) and heart rate (HR) (88.6 ± 15.3 to 49.7 ± 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 ± 226 dyne s/cm⁵) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 ± 6.8 to 89.3 ± 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2–20 min with no differences between treatments. L‐659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral α₂‐adrenoceptors, whereas the effects of verapamil were marginal.     

The α2A‐adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine

Xylazine, the classical α₂‐adrenoceptor (α₂‐AR) agonist, is still used as an analgesic and sedative in veterinary medicine, despite its low potency and affinity for α₂‐ARs. Previous pharmacological studies suggested that the α_2A‐AR subtype plays a role in mediating the clinical effects of xylazine; however, these studies were hampered by the poor subtype‐selectivity of the antagonists used and a lack of knowledge of their bioavailability in vivo. Here, we attempted to elucidate the role of the α_2A‐AR subtype in mediating the clinical effects of xylazine by comparing the analgesic and sedative effects of this drug in wild‐type mice with those in α_2A‐AR functional knockout mice using the hot‐plate and open field tests, respectively. Hippocampal noradrenaline turnover in both mice was also measured to evaluate the contribution of α_2A‐AR subtype to the inhibitory effect of xylazine on presynaptic noradrenaline release. In wild‐type mice, xylazine (10 or 30 mg/kg) increased the hot‐plate latency. Furthermore, xylazine (3 or 10 mg/kg) inhibited the open field locomotor activity and decreased hippocampal noradrenaline turnover. By contrast, all of these effects were abolished in α_2A‐AR functional knockout mice. These results indicate that the α_2A‐AR subtype is mainly responsible for the clinical effects of xylazine.