Different Reactions of Zebra Finches and Bengalese Finches to a Three-Component Mixture of Anesthetics.

Kawai et al. (2011) recently introduced a mixture of three anesthetic agents (here called MMB) that has an effect similar to ketamine/xylazine in mice, which might allow more effective reaction to changes in the animal condition, as an antagonist is available, and which can be used without license for handling narcotic drugs. Using Kawai's study as a baseline, we tested whether this anesthesia and its antagonist can also be used in avian studies. In the present study, we used two species, the zebra finch and the Bengalese finch, of the avian family Estrildidae. In zebra finches, anesthesia effects similar to the use of ketamine/xylazine and to those obtained in mice can be reached by the use of MMB if a higher dose is applied. MMB leads to more variable anesthesia, but has the advantage of a longer time window of deep anesthesia. An antagonist to one component of MMB reduced the awaking time, but was not as effective as in mice. For Bengalese finches, MMB cannot be generally recommended because of difficult handling and high mortality rate when used without antagonist, but could be used for perfusions instead of pentobarbital.

Sedative effect of intramuscular medetomidine with and without vatinoxan (MK-467), and its reversal with atipamezole in sheep.

OBJECTIVE: To evaluate the effect of the peripherally acting α2-adrenoceptor antagonist vatinoxan (MK-467) on the sedative properties of medetomidine (MED) when injected intramuscularly (IM) in the same syringe and on reversal of this sedation with atipamezole in sheep. STUDY DESIGN: Randomized, blinded, crossover experimental trial. ANIMALS: Eight healthy adult female sheep. METHODS: Sheep received MED (30 µg kg-1 IM) alone or combined in the same syringe with vatinoxan (300 µg kg-1 IM, MED+VAT) with a 2 week washout period. Atipamezole (150 µg kg-1 IM) was administered 30 minutes later for reversal. Sedation was assessed using two sedation scores, a visual analog score and a descriptive scale before treatments (T0) and at intervals up to 5 hours thereafter. Pulse rate (PR) was counted at T0 and at 30 (T30) and 90 (T90) minutes. Rectal temperature was measured at T0 and T90 postinjection. Plasma samples were analyzed for drug concentrations at T30 and T90. RESULTS: The first signs of sedation were seen significantly earlier after MED+VAT (4.6 ± 1.7 minutes versus 9.4 ± 2.6 minutes after MED) and the sedation scores were significantly higher after MED+VAT than MED. All animals laid with head down 10.0 ± 3.4 minutes after MED+VAT, whereas three MED animals did not become recumbent before atipamezole was administered. The plasma concentrations of dexmedetomidine were significantly higher at T30 (2.47 ± 0.2 ng mL-1) and significantly lower at T90 (1.23 ± 0.3 ng mL-1) with MED+VAT than with MED (1.19 ± 0.8 and 1.83 ± 0.4 ng mL-1, respectively). While no significant differences were observed between treatments in PR at T30, PR at T90 was significantly higher with MED+VAT than with MED. CONCLUSIONS AND CLINICAL RELEVANCE: When administered IM in the same syringe, vatinoxan hastened and intensified the initial sedative effects of MED and enhanced the sedation reversal by atipamezole.

ECHOCARDIOGRAPHIC PARAMETERS IN EIGHT ADULT TIGERS ( PANTHERA TIGRIS) DURING TWO PHASES OF AN ANESTHETIC PROTOCOL.

Eight adult tigers ( Panthera tigris) underwent a complete echocardiographic examination following sedation with medetomidine, midazolam, and induction of general anesthesia using ketamine and isoflurane (phase 1). Atipamezole was used to antagonize medetomidine (phase 2) and a second echocardiographic examination was performed. Physiologic tricuspid and pulmonic regurgitations were common findings in the sample population and one tiger was excluded from final analyses due to the finding of a ventricular septal defect. Measurements and mean arterial pressure were assessed for statistically significant differences between the two examination phases as well as gender and weight. There was a statistically significant difference between interventricular septum thickness at end systole, ejection fraction, and mean arterial pressure between anesthetic phases while fractional shortening and left ventricular internal dimension at end-systole approached, but did not reach, statistical significance between phases. Weight was found to be a statistically significant predictor of stroke volume and left ventricular internal dimension at end-diastole. The echocardiographic measurements obtained during this study can be used as guidelines for future examinations in adult tigers. The effects of medetomidine on these measurements and systolic function should be taken into account when performing echocardiograms and monitoring anesthetic events.

Propofol-medetomidine-ketamine total intravenous anaesthesia in thiafentanil-medetomidine-immobilized impala (Aepyceros melampus).

OBJECTIVE: To characterize a propofol-medetomidine-ketamine total intravenous anaesthetic in impala (Aepyceros melampus). STUDY DESIGN: Prospective clinical study. ANIMALS: Ten adult female impala. MATERIALS AND METHODS: Impala were immobilized at 1253 m above sea level with 2.0 mg thiafentanil and 2.2 mg medetomidine via projectile darts. Propofol was given to effect (0.5 mg kg-1 boluses) to allow endotracheal intubation, following which oxygen was supplemented at 2 L minute-1. Anaesthesia was maintained with a constant-rate infusion of medetomidine and ketamine at 5 µg kg-1 hour-1 and 1.5 mg kg-1 hour-1, respectively, and propofol to effect (initially 0.2 mg kg-1 minute-1) for 120 minutes. The propofol infusion was titrated according to reaction to nociceptive stimuli every 15 minutes. Cardiopulmonary parameters were monitored continuously and arterial blood gas samples were analysed intermittently. After 120 minutes' maintenance, the thiafentanil and medetomidine were antagonized using naltrexone (10:1 thiafentanil) and atipamezole (5:1 medetomidine), respectively. RESULTS: All impala were successfully immobilized. The median dose [interquartile range (IQR)] of propofol required for intubation was 2.7 (1.9-3.3) mg kg-1. The propofol-medetomidine-ketamine combination abolished voluntary movement and ensured anaesthesia for the 120 minute period. Propofol titration showed a generally downward trend. Median (IQR) heart rate [57 (53-61) beats minute-1], respiratory rate [10 (9-12) breaths minute-1] and mean arterial blood pressure [101 (98-106) mmHg] were well maintained. Arterial blood gas analysis indicated hypoxaemia, hyper- capnia and acidaemia. Butorphanol (0.12 mg kg-1) was an essential rescue drug to counteract thiafentanil-induced respiratory depression. All impala regurgitated frequently during the maintenance period. Recovery was calm and rapid in all animals. Median (IQR) time to standing from antagonist administration was 4.4 (3.2-5.6) minutes. CONCLUSIONS AND CLINICAL RELEVANCE: A propofol-medetomidine-ketamine combination could provide adequate anaesthesia for invasive procedures in impala. The propofol infusion should begin at 0.2 mg kg-1 minute-1 and be titrated to clinical effect. Oxygen supplementation and airway protection with a cuffed endotracheal tube are essential.

Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.

We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 µg/kg) or medetomidine with MK-467 (250 µg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.

Preliminary studies of chemical immobilization of captive juvenile estuarine (Crocodylus porosus) and Australian freshwater (C. johnstoni) crocodiles with medetomidine and reversal with atipamezole.

OBJECTIVE: To establish a safe, reliable and reversible immobilization protocol for captive juvenile crocodiles. STUDY DESIGN: Prospective, randomized, clinical study. ANIMALS: Thirty male estuarine crocodiles (body mass 1-12.1 kg) and 10 male Australian freshwater crocodiles (body mass 4.1-12.8 kg). METHODS: An optimized dose of medetomidine (0.5 mg kg(-1)) was administered intramuscularly (IM) into the tail (Group 1; n = 5), pelvic limb (Group 2; n = 5) and thoracic limb (Groups 3 and 4; n = 5 in each group) of estuarine crocodiles weighing 3-12.1 kg. Their heart and respiratory rates and degree of immobilization were monitored every 15 minutes until recovery and daily thereafter for 3 subsequent days. In Group 4 (n = 5), medetomidine was antagonized with an optimized dose of atipamezole (2.5 mg kg(-1)) given IM into the thoracic limb and time to recovery recorded. The effects of increasing doses of medetomidine given IM in the thoracic limb (n = 4) and intravenously (n = 6) were determined in 1-2 kg estuarine crocodiles. Australian freshwater crocodiles (4.1-12.8 kg) were administered medetomidine IM into the thoracic limb in divided doses at 0.5 mg kg(-1) (n = 5) and 0.75 mg kg(-1) (n = 5) and similarly monitored. RESULTS: Immobilization was achieved only in the estuarine crocodiles >3 kg and when medetomidine was administered into the thoracic limb. Immobilization was achieved within 30 minutes and the duration of immobilization lasted approximately 90 minutes. Immobilization in estuarine crocodiles was readily reversed with atipamezole. A dose of 0.75 g kg(-1) was required to immobilize Australian freshwater crocodiles and the onset of immobilization was longer and the duration shorter than seen in the estuarine crocodiles. The heart and respiratory rates of all immobilized animals decreased significantly and arterial blood pressure became undetectable in the animals in which it was measured. CONCLUSIONS AND CLINICAL RELEVANCE: Medetomidine administered in the thoracic limb of captive estuarine and Australian freshwater crocodiles, ranging from 3 to 12.8 kg, provides a predictable onset and duration of immobilization sufficient for physical examination, sample collection, short minor procedures and translocation of the animals. Atipamezole administered in the thoracic limb results in complete reversal of the effects of medetomidine in the estuarine crocodile and a rapid return to normal behaviour.

Reversible immobilization of free-ranging Svalbard reindeer (Rangifer tarandus platyrhynchus) with medetomidine-ketamine and atipamezole.

Twenty adult, free-ranging, female Svalbard reindeer (Rangifer tarandus platyrhynchus) were immobilized with medetomidine-ketamine from 30 September through 9 October 1999 at Svalbard, Norway (78 degrees 55'N, 11 degrees 56'E). The animals were approached on foot, and the drugs were administered into the heavy muscles of the shoulder or the thigh by dart syringe injection from 15-25 m. The mean (SD) induction time in 10 animals immobilized with 0.113 (0.009) mg/kg of medetomidine and 2.26 (0.19) mg/kg of ketamine (group 2) was significantly shorter (P < 0.05) than in 10 animals immobilized with 0.215 (0.043) mg/kg of medetomidine and 1.08 (0.21) mg/kg of ketamine (group 1): 6.5 (3.2) versus 14.3 (10.6) min, respectively. Inductions were calm, major clinical side effects were not detected, and there were no significant differences between groups regarding rectal temperature, pulse rate, respiratory rate, or relative arterial oxygen saturation. The 5 mg of atipamezole/1 mg of medetomidine were given half intramuscularly and half subcutaneously for reversal, and the animals were standing within 9.5 (4.5, group 1) and 13.0 (6.4, group 2) min, respectively, after administration of the antagonist.

Effects of an anesthetic mixture of medetomidine, midazolam, and butorphanol and antagonism by atipamezole in rabbits.

Medetomidine (MED), midazolam (MID), and butorphanol (BUT) mixed anesthetic (MMB) has been used in laboratory animals since ketamine (KET) was designated as a narcotic in Japan in 2007. We previously reported that MMB produced anesthetic effects in mice and rats. We also demonstrated the efficacy of atipamezole (ATI), an antagonist of MED produced a quick recovery from anesthesia. Anesthetics have various anesthetic effects among different animal species. However, there is little information regarding its effects in rabbits. In the present study, we examined anesthetic effects of MMB compared to KET and xylazine mixed anesthetic (KX). We examined the antagonistic effects of ATI by intramuscular (IM) or intravenous (IV) injection in rabbits. We used the anesthetic score to measure surgical anesthetic duration and recovery time from anesthesia. During the experiments, we measured heart rate, respiratory rate, O2-saturation, and blood pressure. We found there were no significant differences in anesthetic duration and recovery time between MMB and KX. There were no significant differences in heart rate after administration of MMB or KX. Systolic blood pressure at 10 min after administration of MMB was higher than that of KX. The antagonistic effect of ATI by IV injection worked faster than that by IM injection. Overall, MMB is a useful drug that can induce similar anesthetic effects to KX and has an antagonist of ATI that makes rabbits quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals, especially rabbits.

Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2-adrenoceptor antagonist vatinoxan hydrochloride.

OBJECTIVE: To investigate the cardiovascular and sedation reversal effects of IM administration of atipamezole (AA) in dogs treated with medetomidine hydrochloride (MED) or MED and vatinoxan (MK-467). ANIMALS: 8 purpose-bred, 2-year-old Beagles. PROCEDURES: A randomized, blinded, crossover study was performed in which each dog received 2 IM treatments at a ≥ 2-week interval as follows: injection of MED (20 µg/kg) or MED mixed with 400 µg of vatinoxan/kg (MEDVAT) 30 minutes before AA (100 µg/kg). Sedation score, heart rate, mean arterial and central venous blood pressures, and cardiac output were recorded before and at various time points (up to 90 minutes) after AA. Cardiac and systemic vascular resistance indices were calculated. Venous blood samples were collected at intervals until 210 minutes after AA for drug concentration analysis. RESULTS: Heart rate following MED administration was lower, compared with findings after MEDVAT administration, prior to and at ≥ 10 minutes after AA. Mean arterial blood pressure was lower with MEDVAT than with MED at 5 minutes after AA, when its nadir was detected. Overall, cardiac index was higher and systemic vascular resistance index lower, indicating better cardiovascular function, in MEDVAT-atipamezole-treated dogs. Plasma dexmedetomidine concentrations were lower and recoveries from sedation were faster and more complete after MEDVAT treatment with AA than after MED treatment with AA. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole failed to restore heart rate and cardiac index in medetomidine-sedated dogs, and relapses into sedation were observed. Coadministration of vatinoxan with MED helped to maintain hemodynamic function and hastened the recovery from sedation after AA in dogs.

Antagonistic effects of atipamezole, flumazenil and 4-aminopyridine against anaesthesia with medetomidine, midazolam and ketamine combination in cats.

Antagonistic effects of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP) alone and in various combinations after administration of medetomidine-midazolam-ketamine (MED-MID-KET) were evaluated in cats. Animals were anaesthetised with MED (50 microg/kg), MID (0.5 mg/kg) and KET (10 mg/kg) given intramuscularly. Twenty minutes later, physiological saline, ATI (200 microg/kg), FLU (0.1 mg/kg), 4AP (0.5 mg/kg), ATI-FLU, FLU-4AP, ATI-4AP or ATI-FLU-4AP was administered intravenously. FLU, 4AP alone, or FLU-4AP did not effectively antagonise the anaesthesia, hypothermia, bradycardia, and bradypnoea induced by MED-MID-KET. ATI alone was effective. ATI-FLU, ATI-4AP and ATI-FLU-4AP combinations produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-4AP was the most effective in antagonising the anaesthetic effects, but was associated with tachycardia, tachypnoea, excitement, and muscle tremors. Combinations with ATI are more effective for antagonising anaesthesia, but ATI-FLU-4AP is not suitable.

Sedative and cardiopulmonary effects of medetomidine hydrochloride and xylazine hydrochloride and their reversal with atipamezole hydrochloride in calves.

OBJECTIVE: To assess the sedative and cardiopulmonary effects of medetomidine and xylazine and their reversal with atipamezole in calves. ANIMALS: 25 calves. PROCEDURES: A 2-phase (7-day interval) study was performed. Sedative characteristics (phase I) and cardiopulmonary effects (phase II) of medetomidine hydrochloride and xylazine hydrochloride administration followed by atipamezole hydrochloride administration were evaluated. In both phases, calves were randomly allocated to receive 1 of 4 treatments IV: medetomidine (0.03 mg/kg) followed by atipamezole (0.1 mg/kg; n = 6), xylazine (0.3 mg/kg) followed by atipamezole (0.04 mg/kg; 7), medetomidine (0.03 mg/kg) followed by saline (0.9% NaCl; 6) solution (10 mL), and xylazine (0.3 mg/kg) followed by saline solution (10 mL; 6). Atipamezole or saline solution was administered 20 minutes after the first injection. Cardiopulmonary variables were recorded at intervals for 35 minutes after medetomidine or xylazine administration. RESULTS: At the doses evaluated, xylazine and medetomidine induced a similar degree of sedation in calves; however, the duration of medetomidine-associated sedation was longer. Compared with pretreatment values, heart rate, cardiac index, and PaO(2) decreased, whereas central venous pressure, PaCO(2), and pulmonary artery pressures increased with medetomidine or xylazine. Systemic arterial blood pressures and vascular resistance increased with medetomidine and decreased with xylazine. Atipamezole reversed the sedative and most of the cardiopulmonary effects of both drugs. CONCLUSIONS AND CLINICAL RELEVANCE: At these doses, xylazine and medetomidine induced similar degrees of sedation and cardiopulmonary depression in calves, although medetomidine administration resulted in increases in systemic arterial blood pressures. Atipamezole effectively reversed medetomidine- and xylazine-associated sedative and cardiopulmonary effects in calves.

Effects of an anesthetic mixture of medetomidine, midazolam, and butorphanol in rats-strain difference and antagonism by atipamezole.

An anesthetic mixture of medetomidine (MED), midazolam (MID), and butorphanol (BUT) has been used in laboratory animals. We previously reported that this anesthetic mixture produced closely similar anesthetic effects in BALB/c and C57BL/6J strains. We also demonstrated the efficacy of atipamezole (ATI), an antagonist of MED that produced quick recovery from anesthesia in mice. Anesthetics have various anesthetic effects among animal strains. However, the differences in the effects of anesthetic mixtures in rats are unclear. In the present study, we first examined effects of the abovementioned anesthetic mixture using three different rat strains: Wistar (WST), Sprague-Dawley (SD), and Fischer 344 (F344). Second, we examined how different dosages and optimum injection timing of ATI affected recovery from anesthesia in rats. We used the anesthetic score to measure anesthetic duration and a pulse oximeter to monitor vital signs. We found no significant differences in anesthetic duration among the three different strains. However, recovery from anesthesia in the SD strain took significantly longer than in the other strains. The antagonistic effects of ATI (0.15 mg/kg and 0.75 mg/kg) were equivalent when administered at 30 min after anesthetic mixture administration. The antagonistic effects of ATI 0.75 mg/kg were stronger than those of ATI 0.15 mg/kg at 10 min after anesthetic mixture administration. This anesthetic mixture is a useful drug that can induce similar anesthetic effects in three different strains and has an antagonist, ATI, that makes rats quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals.

Injection anaesthesia with fentanyl-midazolam-medetomidine in adult female mice: importance of antagonization and perioperative care.

Injection anaesthesia is commonly used in laboratory mice; however, a disadvantage is that post-anaesthesia recovery phases are long. Here, we investigated the potential for shortening the recovery phase after injection anaesthesia with fentanyl-midazolam-medetomidine by antagonization with naloxone-flumazenil-atipamezole. In order to monitor side-effects, the depth of anaesthesia, heart rate (HR), core body temperature (BT) and concentration of blood gases, as well as reflex responses, were assessed during a 50 min anaesthesia. Mice were allowed to recover from the anaesthesia in their home cages either with or without antagonization, while HR, core BT and spontaneous home cage behaviours were recorded for 24 h. Mice lost righting reflex at 330 ± 47 s after intraperitoneal injection of fentanyl-midazolam-medetomidine. During anaesthesia, HR averaged 225 ± 23 beats/min, respiratory rate and core BT reached steady state at 131 ± 15 breaths/min and 34.3 ± 0.25℃, respectively. Positive pedal withdrawal reflex, movement triggered by tail pinch and by toe pinch, still occurred in 25%, 31.2% and 100% of animals, respectively. Arterial blood gas analysis revealed acidosis, hypoxia, hypercapnia and a marked increase in glucose concentration. After anaesthesia reversal by injection with naloxone-flumazenil-atipamezole, animals regained consciousness after 110 ± 18 s and swiftly returned to physiological baseline values, yet they displayed diminished levels of locomotion and disrupted circadian rhythm. Without antagonization, mice showed marked hypothermia (22 ± 1.9℃) and bradycardia (119 ± 69 beats/min) for several hours. Fentanyl-midazolam-medetomidine provided reliable anaesthesia in mice with reasonable intra-anaesthetic side-effects. Post-anaesthetic period and related adverse effects were both reduced substantially by antagonization with naloxone-flumazenil-atipamezole.

Use of medetomidine-ketamine and atipamezole for reversible immobilization of free-ranging hog deer (Axis porcinus) captured in drive nets.

A combination of 0.05 mg/kg medetomidine and 1.5 mg/kg ketamine was used to immobilize nine adult free-ranging hog deer (Axis porcinus) captured in drive nets in the Royal Bardia National Park, Nepal, 22-23 February 2000. The drugs were administered intramuscularly from separate syringes and the mean time (+/-SD) to complete immobilization was 4.6+/-1.0 min. Muscle relaxation was good and no major clinical side effects were seen. Mean values for physiologic parameters, recorded at 10-12 and 18-20 min after drug administration, were 40.6+/-0.5 and 41.1+/-0.6 C, 87+/-5 and 84+/-4%, 107+/-16 and 113+/-16 beats/ min, and 46+/-9 and 40+/-8 breaths/min for rectal temperature, SpO2, pulse rate, and respiratory rate, respectively. All animals received 0.25 mg/ kg atipamezole intramuscularly 20-22 min after administration of medetomidine-ketamine and the mean time to coordinated running was 4.8+/-0.8 min. All animals survived for at least 5 mo post-capture. To reduce stress and to facilitate handling, medetomidine-ketamine and atipamezole are recommended for reversible immobilization of free-ranging hog deer captured in drive nets.

Anesthetic effects of a three-drugs mixture--comparison of administrative routes and antagonistic effects of atipamezole in mice.

The anesthetic mixture of medetomidine (MED), midazolam (MID) and butorphanol (BUT) produced anesthetic duration of around 40 minutes (min) in ICR mice. We reported that this anesthetic mixture produced almost the same anesthetic effects in both male and female BALB/c and C57BL/6J strains. Intraperitoneal (IP) administration of drugs has been widely used in mice. However, various injectable routes of the anesthetic mixture may cause different anesthetic effects. First, we examined effects of the anesthetic mixture by subcutaneous (SC) and intravenous (IV) injection compared to IP injection. After injection of the anesthetic mixture, administration of atipamezole (ATI) induced mice recovery from anesthesia. Secondly, we examined how different dosage and optimum injection timing of ATI affected mice recovery from anesthesia. We used an anesthetic score to measure anesthetic duration and a pulse oximeter to monitor vital signs under anesthesia. Usually, drugs from SC injection work more weakly than IP or IV injection. However, we found no significant differences of anesthetic duration among the three different injection routes. Antagonistic effects of ATI (0.3 mg/kg and 1.5 mg/kg) worked equally when administered at 30 min after injection of the anesthetic mixture. Antagonistic effects of ATI (1.5 mg/kg) were stronger than ATI (0.3 mg/kg) at 10 min after injection of the anesthetic mixture. The anesthetic mixture is a useful drug to induce nearly the same anesthetic effects by different injection routes and has an antagonist of ATI which helps mice quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals.

Occurrence, pharmacology and function of presynaptic alpha2-autoreceptors in alpha2A/D-adrenoceptor-deficient mice.

The occurrence, pharmacological properties and function of alpha2-autoreceptors were studied in hippocampal slices, occipito-parietal cortex slices, segments of heart atria and segments of the vas deferens of wildtype (WT) mice and mice in which the alpha2 A/D-adrenoceptor gene had been disrupted (alpha2 A/D(KO)). Tissues were preincubated with [3H]-noradrenaline and then superfused and stimulated electrically. Stimulation periods for brain slices consisted either of 1 pulse or of 2-64 pulses delivered at 1-s intervals; stimulation periods for peripheral tissues consisted either of 1 POP (pseudo-one-pulse; brief burst of 20 pulses/50 Hz) or of 2-4 POPs delivered at 1-s intervals. Single pulses or POPs were used to study the effect of medetomidine and its interaction with antagonists. One or more pulses or POPs per stimulation period were used to study alpha2-autoinhibition. Medetomidine decreased the evoked overflow of tritium in WT tissues. In alpha2 A/D(KO) tissues, the inhibition was slightly (peripheral tissues) or greatly (brain slices) attenuated but not abolished. Phentolamine, rauwolscine, spiroxatrine, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), tolazoline and prazosin antagonized the effect of medetomidine in all tissues. Their pKd values against medetomidine were compared with pKd values at prototypical alpha2 binding sites by means of a correlation analysis. For WT brain and atrial autoreceptors, the correlations indicated an alpha2D pharmacology, whereas for WT vas deferens autoreceptors they favoured an alpha2B pharmacology. In the KO tissues, any correlation with alpha2D was lost, and the non-alpha2 A/D-autoreceptors displayed alpha2B or alpha2C pharmacology. When 2 or more pulses or POPs were applied to WT tissues per stimulation period, the pulse number-overflow curve (POP number-overflow curve) was flat, indicating that overflow elicited by p pulses (POPs) was much smaller than p times the overflow elicited by a single pulse (POP); moreover, rauwolscine caused a pulse (POP) number-dependent and, at high pulse (POP) numbers, large increase in evoked tritium overflow. In alpha2 A/D(KO) tissues, the pulse (POP) number-overflow curve was much steeper, indicating that overflow elicited by p pulses (POPs) was closer to p times the overflow elicited by a single pulse (POP); moreover, rauwolscine caused no (atria) or only a small increase in overflow, and did so in brain slices only at high pulse numbers (16 and 64). In conclusion, the predominant alpha2D pharmacology of the autoreceptors in WT tissues supports the idea that the main mammalian presynaptic alpha2-autoreceptors belong to the alpha2 A/D subtype. However, alpha2 A/D-deficient animals also possess autoreceptors. As expected, these non-alpha2 A/D-autoreceptors display alpha2B or alpha2C pharmacology. In WT animals, alpha2B- or alpha2C-autoreceptors or both may coexist with alpha2 A/D-autoreceptors, at least in peripheral tissues. Little autoinhibition by released noradrenaline in trains of pulses remains when the alpha2 A/D-adrenoceptor is lacking, again in accord with a predominance of alpha2 A/D-autoreceptors.

Reversal of medetomidine-ketamine combination anesthesia in rabbits by atipamezole.

This study was performed to determine the optimal reversal dosage of atipamezole on medetomidine-ketamine combination anesthesia. The subject rabbits were divided into five groups (n=5/group), and all were anesthetized with intravenous medetomidine (0.35 mg/kg) and ketamine (5 mg/kg). Atipamezole was administered intravenously 35 min after administration of the medetomidine-ketamine mixture, at doses of a quarter, a half, equal, or two times higher than the preceding medetomidine -ketamine dose according to experimental group. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and rectal temperature (RT) were measured every five minutes and the mean arousal time (MAT) was also recorded. This study revealed that the optimal atipamezole dosage to achieve reversal effects is equal to or double the dose of medetomidine. At these dosages, HR and MAP significantly recovered and MAT was significantly shortened with no side effects being observed (p<0.05).

The antagonistic effects of atipamezole and yohimbine on stress-related neurohormonal and metabolic responses induced by medetomidine in dogs.

This study aimed to compare the antagonistic effects of atipamezole (40,120, and 320 microg/kg, IM), yohimbine (110 microg/kg, IM), and saline on neurohormonal and metabolic responses induced by medetomidine (20 microg/kg, IM). Five beagle dogs were used in each of the 5 experimental groups in randomized order. Blood samples were taken for 6 h. Medetomidine significantly decreased norepinephrine, epinephrine, insulin, and nonesterified fatty acid levels, and increased plasma glucose levels. Both atipamezole and yohimbine antagonized these effects. The reversal effect of atipamezole was dose-dependency, except on epinephrine. Yohimbine caused prolonged increases in plasma norepinephrine and insulin levels compared to atipamezole, possibly because of its longer half-life elimination. Only yohimbine increased the cortisol levels. Neither glucagon nor lactate levels changed significantly. Based on these findings, when medetomidine-induced sedation is antagonized in dogs, we recommend using atipamezole IM, from 2- to 6-fold the dose of medetomidine, unless otherwise indicated.

Sufentanil and medetomidine anaesthesia in the rat and its reversal with atipamezole and butorphanol.

Injectable anaesthetics are widely used to anaesthetize rats, but recovery times are often prolonged. Reversible anaesthetic regimens have the advantage that animals may be recovered quickly, thus reducing the incidence of postoperative complications such as hypothermia, and also providing a means of treating inadvertent anaesthetic overdose. This study assessed and compared the characteristics of anaesthesia induced with combinations of sufentanil and medetomidine administered as a single subcutaneous or intraperitoneal dose, and reversal with butorphanol and atipamezole. Combinations of sufentanil/medetomidine at 40 microg/150 microg and 50 microg/150 microg/kg administered subcutaneously, and 80 microg/300 microg/kg by intraperitoneal injection were found to produce surgical anaesthesia for 101+/-49, 124+/-45 and 76+/-23 min (means +/- SD) respectively. All three combinations produced marked respiratory depression 30 min after injection (< 50% of resting respiratory rate). Oxygen saturation, measured by pulse oximetry, was < 50% in all groups 30 min following drug administration. Subcutaneous administration is recommended since it resulted in a more reliable and more rapid induction of anaesthesia than intraperitoneal administration. The administration of butorphanol and atipamezole (0.2/0.5 mg/kg s.c.) resulted in a rapid (< 7 min) reversal of anaesthesia and an associated respiratory depression. The induction of anaesthesia with sufentanil/medetomidine and its reversal with a combination of atipamezole and butorphanol is an effective technique for anaesthetizing rats. However, due to the marked respiratory depression and the resulting hypoxia, we recommend that this regimen should only be used in animals which are free from respiratory disease and that oxygen should be provided during anaesthesia.

Immobilization of sika deer with medetomidine and ketamine, and antagonism by atipamezole.

Forty wild sika deer (Cervus nippon) were immobilized with medetomidine and ketamine and reversed by atipamezole in summer and fall captures from September 1994 to October 1995. For large yearling and older deer, mean +/- SD doses of 57.0+/-15.6 microg/kg medetomidine and 1.64+/-0.49 mg/kg (male) or 4.02+/-1.16 mg/kg (female) of ketamine were administered by intramuscular injection. For calves and small yearlings, 69.3+/-7.0 microg/kg medetomidine and 2.69+/-0.44 mg/kg ketamine were administered. While immobilized, deer were easy to handle, and muscles were well relaxed. After intramuscular administration of atipamezole (about 5 times the dose of medetomidine), deer recovered rapidly and smoothly.