Alpha-2 adronoceptor agonists and antagonists in animals

Background: The oral sugar test (OST) is commonly used to diagnose insulin dysregulation (ID) and equine metabolic syndrome; however, possible seasonal changes in OST results have not been evaluated. Objective: To determine the possible variation in insulin response to OST throughout the year and risk factors associated with maximum insulin concentration (InsMax) and ID. Study design: Prospective, longitudinal cohort study. Methods: The oral sugar test was performed on 29 Finnhorses every other month six times. Serum total adiponectin concentration and phenotypic variables related to obesity were also measured. Changes in InsMax, adiponectin, scale weight, body condition score, cresty neck score, and fasting glucose concentration were assessed. Risk factor analyses were performed on InsMax and ID status, and ID groups were compared with each other. Results: Fourteen horses were categorised with non-ID each time and 15 as having ID at least once during the follow-up period. The ID status of 12 horses varied throughout the year, but neither the insulin variables measured during the OST nor adiponectin expressed significant seasonal variation. Increasing age and cresty neck score, and decreasing adiponectin were observed as risk factors for a high InsMax after OST. The risk of ID was higher in horses with no exercise compared to horses with exercise (OR 7.6, 95% CI 1.2-49.3, p = 0.03). Horses with ID had lower serum adiponectin concentrations, longer neck circumference and larger height than horses in the non-ID group. Main limitations: The environmental conditions (feeding, exercise) were not constant for all horses throughout the study and only one breed was used. Conclusions: Neither OST results nor adiponectin varies with season; however, there were a substantial number of horses with variable ID status throughout the year, in which repeated OSTs may be beneficial. Lack of exercise was a risk factor for ID.

Objective To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration. Study design A randomized, controlled, blinded, clinical trial. Animals A total of 28 client-owned dogs. Methods Dogs were premedicated with medetomidine (0.125 mg m⁻²) and butorphanol (0.2 mg kg⁻¹) (group MB; n = 14), or medetomidine (0.25 mg m⁻²), butorphanol (0.2 mg kg⁻¹) and vatinoxan (5 mg m⁻²) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg⁻¹) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg⁻¹) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (fR), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (Fe′Sevo) and carbon dioxide (Pe′CO2) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations. Results At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute⁻¹ (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in fR, Pe′CO2, Fe′Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups. Conclusions and clinical relevance In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.

Objective To determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs given dexmedetomidine with vatinoxan. Study design Balanced, randomised crossover trial. Animals A total of eight healthy Beagle dogs. Methods Each dog was anaesthetized with isoflurane (end-tidal isoflurane 1.3%) and five treatments: dexmedetomidine hydrochloride (2.5 μg kg⁻¹) bolus followed by 0.9% saline infusion (DEX-S); dexmedetomidine and vatinoxan hydrochloride (100 μg kg⁻¹) bolus followed by an infusion of 0.9% saline (DEX-VAT-S), dobutamine (DEX-VAT-D), norepinephrine (DEX-VAT-N) or phenylephrine (DEX-VAT-P). The dexmedetomidine and vatinoxan boluses were administered at T0 and the treatment infusion was started after 15 minutes (T15) if mean arterial pressure (MAP) was < 90 mmHg. The treatment infusion rate was adjusted every 5 minutes as required. Systemic haemodynamics were recorded at T0 and 10 (T10) and 45 (T45) minutes. A repeated measures analysis of covariance model was used. Results Most dogs had a MAP < 70 mmHg at T0 before treatment. Both DEX-S and all DEX-VAT treatments significantly increased MAP at T10, but systemic vascular resistance index (SVRI) was significantly higher and cardiac index (CI) lower after DEX-S than DEX-VAT. CI did not significantly differ between DEX-S and DEX-VAT-S at T45 while SVRI remained higher with DEX-S. Normotension was achieved by all vasoactive infusions in every dog, whereas MAP was below baseline with DEX-VAT-S, and higher than baseline with DEX-S at T45. The median infusion rates were 3.75, 0.25 and 0.5 μg kg⁻¹ minute⁻¹ for dobutamine, norepinephrine and phenylephrine, respectively. Dobutamine and norepinephrine increased CI (mean ± standard deviation, 3.35 ± 0.70 and 3.97 ± 1.24 L minute⁻¹ m⁻², respectively) and decreased SVRI, whereas phenylephrine had the opposite effect (CI 2.13 ± 0.45 L minute⁻¹ m⁻²). Conclusions and clinical relevance Hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine and vatinoxan can be treated with either dobutamine or norepinephrine.

Background: The potent sedative medetomidine is a commonly used adjunct for the immobilisation of non-domestic mammals. However, its use is associated with pronounced cardiovascular side effects, such as bradycardia, vasoconstriction and decreased cardiac output. We investigated the effects of the peripherally-acting alpha-2-adrenoceptor antagonist vatinoxan on cardiovascular properties in medetomidine-tiletamine-zolazepam anaesthetised wild boar (Sus scrofa). Methods: Twelve wild boars, anaesthetised twice with medetomidine (0.1 mg/kg) and tiletamine/zolazepam (2.5 mg/kg) IM in a randomised, crossover study, were administered (0.1 mg/kg) vatinoxan or an equivalent volume of saline IV (control). Cardiovascular variables, including heart rate (HR), mean arterial blood pressure (MAP), pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP) and cardiac output (CO), were assessed 5 min prior to vatinoxan/saline administration until the end of anaesthesia 30 min later. Results: MAP (p < 0.0001), MPAP (p < 0.001) and MPAOP (p < 0.0001) significantly decreased from baseline after vatinoxan until the end of anaesthesia. HR increased significantly (p < 0.0001) from baseline after vatinoxan administration. However, the effect on HR subsided 3 min after vatinoxan. All variables remained constant after saline injection. There was no significant effect of vatinoxan or saline on CO. Conclusion: Vatinoxan significantly reduced systemic and pulmonary artery hypertension, induced by medetomidine in wild boar.

It was hypothesized that premedication with vatinoxan, a peripheral α2-adrenoceptor antagonist, would mitigate xylazine-induced pulmonary alterations in sheep. Fourteen adult sheep were allotted into two equal groups and premedicated with either vatinoxan (750 µg/kg IV) or saline and sedated 10 min later with xylazine (500 µg/kg IV). Arterial oxygen saturation (SpO2) was measured and respiratory rate (RR) counted at intervals. The sheep were euthanized with IV pentobarbital 10 min after xylazine administration. The severity of pulmonary parenchymal alterations was assessed and graded grossly and histologically and correlations of the morphological changes with SpO2 evaluated. Following xylazine injection, SpO2 was significantly higher and RR significantly lower with vatinoxan than with saline and the sheep administered vatinoxan exhibited significantly smaller quantities of tracheal foam than those receiving saline. No significant differences in macroscopic oedema scores were detected between treatments. In contrast, the vatinoxan-treated animals exhibited significantly graver microscopic interstitial alveolar oedema and haemorrhage than saline-treated animals. The histological severity scores did not correlate with changes in SpO2. In conclusion, xylazine induced a marked reduction in SpO2 which was abolished by the prior administration of vatinoxan. The histologically detected alterations after pentobarbital euthanasia with vatinoxan premedication need to be studied further.

Objectives To investigate the extent of vatinoxan distribution into sheep brain, and whether vatinoxan influences brain concentrations of xylazine. To examine the utility of cerebrospinal fluid (CSF) as a surrogate of brain tissue concentrations for vatinoxan and xylazine. Study design Randomized, blinded, experimental study. Animals A total of 14 adult female sheep. Methods Sheep were randomly allocated into two equal groups and premedicated with either intravenous (IV) vatinoxan (750 μg kg⁻¹, VX) or saline (SX) administered 10 minutes before IV xylazine (500 μg kg⁻¹). Sedation was subjectively assessed at selected intervals before and after treatments. At 10 minutes after xylazine administration, a venous blood sample was collected and the sheep were immediately euthanized with IV pentobarbital (100 mg kg⁻¹). Plasma, CSF and brain tissues were harvested and concentrations of vatinoxan and xylazine were quantified by liquid chromatography–tandem mass spectrometry. Drug ratios were then calculated and the data were analyzed as appropriate. Results The brain-to-plasma and CSF-to-plasma ratios of vatinoxan were 0.06 ± 0.013 and 0.05 ± 0.01 (mean ± standard deviation), respectively. Xylazine brain concentrations were not significantly different (835 ± 262 versus 1029 ± 297 ng g⁻¹ in groups VX and SX, respectively) and were approximately 15-fold higher than those in plasma. The CSF-to-brain ratio of vatinoxan was 0.8 ± 0.2, whereas xylazine concentrations in the brain were approximately 17-fold greater than those in CSF, with and without vatinoxan. Conclusion and clinical relevance Vatinoxan did not significantly affect the sedation with xylazine or the concentrations of xylazine in the brain. CSF is not a good predictor of xylazine concentrations in the brain, whereas vatinoxan concentrations were concordant between the brain and CSF, using the dosages in this study.

Objective To compare the sedative effects of intramuscular xylazine alone or combined with levomethadone or ketamine in calves before cautery disbudding. Study design Randomized, blinded, clinical trial. Animals A total of 28 dairy calves, aged 21 ± 5 days, weight 61.0 ± 9.3 kg (mean ± standard deviation). Methods Calves were randomly allocated to three groups: xylazine (0.1 mg kg⁻¹) and levomethadone (0.05 mg kg⁻¹; group XL), xylazine (0.1 mg kg⁻¹) and ketamine (1 mg kg⁻¹; group XK) and xylazine alone (0.2 mg kg⁻¹; group X). Local anaesthesia (procaine hydrochloride) and meloxicam were administered subcutaneously 15 minutes after sedation and 15 minutes before disbudding. The calves’ responses to the administration of local anaesthesia and disbudding were recorded. Sedation scores were evaluated at baseline and at intervals up to 240 minutes postsedation. Times of recumbency, first head lift and first standing were recorded. Drug plasma concentrations were measured. Results Data were obtained from 27 animals. All protocols resulted in sedation sufficient to administer local anaesthesia and to perform disbudding. Sedation scores significantly correlated with drug plasma concentrations (p ≤ 0.002). Times to recumbency did not differ among protocols (2.8 ± 0.3, 3.1 ± 1.1 and 2.1 ± 0.8 minutes for groups XL, XK and X, respectively), whereas interval from drug(s) administration until first head lift was significantly shorter in group XK than X (47.3 ± 14.1, 34.4 ± 5.3 and 62.6 ± 31.9 minutes for groups XL, XK and X, respectively). The area under the time-sedation curve was significantly greater in group X than XK or XL (754 ± 215, 665 ± 118 and 1005 ± 258 minutes for groups XL, XK and X, respectively). Conclusion and clinical relevance Levomethadone or ketamine with a low dose of xylazine produced short but sufficient sedation for local anaesthesia and disbudding with minimum resistance.

Objective To compare the cardiovascular and ventilatory effects, immobilization quality and the effects on tissue perfusion of a medetomidine-ketamine-midazolam combination with or without vatinoxan (MK-467), a peripherally acting α2-adrenoceptor antagonist. Study design Randomized, blinded cross-over study. Animals A group of nine healthy Patagonian maras (Dolichotis patagonum). Methods Maras were immobilized twice with either: 1) medetomidine hydrochloride (0.1 mg kg⁻¹) + ketamine (5 mg kg⁻¹) + midazolam (0.1 mg kg⁻¹) (MKM) + saline, or with 2) MKM + vatinoxan hydrochloride (0.8 mg kg⁻¹), administered intramuscularly. Drugs were mixed in the same syringe. At 20, 30 and 40 minutes after injection, invasive blood pressure, heart rate, respiration rate, end-tidal CO2, haemoglobin oxygen saturation, arterio-venous oxygen content difference, and muscle oxygenation were measured. Muscle tone, jaw tone, spontaneous blinking and palpebral reflex were evaluated. Times to initial effect, recumbency, initial arousal and control of the head were recorded. Paired t-test, Wilcoxon matched-pairs signed rank test and ANOVA were used to compare protocols. p < 0.05 was considered significant. Results Vatinoxan significantly reduced systolic (p = 0.0002), mean (p < 0.0001) and diastolic (p < 0.0001) arterial blood pressures between 20 and 40 minutes. Mean arterial blood pressures (MAPs) at 30 minutes (mean ± standard deviation) with MKM and MKM + vatinoxan were 105 ± 12 mmHg and 71 ± 14 mmHg, respectively. Without vatinoxan, four animals were hypertensive (MAP > 120 mmHg) while with vatinoxan, four animals were hypotensive (MAP < 60 mmHg). Muscle and jaw tone were significantly more frequently present with MKM (both p = 0.039). Other measurements did not significantly differ between protocols. Conclusion and clinical relevance In Patagonian maras, vatinoxan attenuated the increase in blood pressure induced by medetomidine. Muscle and jaw tone were more frequently present with MKM, indicating that quality of immobilization with vatinoxan was more profound.

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0, 1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values ≤0.05 were considered significant. Comparing DET vs. SAL and DET vs. DET + VAT, insulin was higher at 2 h in the non-ID group and 2 and 4 h in the ID group. There was no difference in insulin between SAL and DET + VAT or VAT. Comparing DET vs. SAL, BG was higher at 1 and 2 h then was lower at 4 h in both ID and non-ID groups. At 1 h in both groups, BG after DET + VAT was lower than after DET but higher than after SAL. Comparing DET vs. SAL, glucagon was lower at 1 h in the ID group and 1 and 2 h in the non-ID group. Vatinoxan was effective in preventing detomidine-induced hyperglycaemia as well as the subsequent insulin increase in horses with ID.

Objective To evaluate the effects of combined infusions of vatinoxan and dexmedetomidine on inhalant anesthetic requirement and cardiopulmonary function in dogs. Study design Prospective experimental study. Methods A total of six Beagle dogs were anesthetized to determine sevoflurane minimum alveolar concentration (MAC) prior to and after an intravenous (IV) dose (loading then continuous infusion) of dexmedetomidine (4.5 μg kg⁻¹ hour⁻¹) and after two IV doses of vatinoxan in sequence (90 μg kg⁻¹ hour⁻¹ and 180 μg kg⁻¹ hour⁻¹). Blood was collected for plasma dexmedetomidine and vatinoxan concentrations. During a separate anesthesia, cardiac output (CO) was measured under equivalent MAC conditions of sevoflurane and dexmedetomidine, and then with each added dose of vatinoxan. For each treatment, cardiovascular variables were measured with spontaneous and controlled ventilation. Repeated measures analyses were performed for each response variable, and for all analyses, p < 0.05 was considered significant. Results Dexmedetomidine reduced sevoflurane MAC by 67% (0.64 ± 0.1%) mean ± standard deviation in dogs. The addition of vatinoxan attenuated this to 57% (0.81 ± 0.1%) and 43% (1.1 ± 0.1%) with low and high doses, respectively, and caused a reduction in plasma dexmedetomidine concentrations. Heart rate and CO decreased while systemic vascular resistance increased with dexmedetomidine regardless of ventilation mode. The co-administration of vatinoxan dose-dependently modified these effects such that cardiovascular variables approached baseline. Conclusions and clinical relevance IV infusions of 90 and 180 μg kg⁻¹ hour⁻¹ of vatinoxan combined with 4.5 μg kg⁻¹ hour⁻¹ dexmedetomidine provides a meaningful reduction in sevoflurane requirement in dogs. Although sevoflurane MAC sparing properties of dexmedetomidine in dogs are attenuated by vatinoxan, the cardiovascular function is improved. Doses of vatinoxan > 180 μg kg⁻¹ hour⁻¹ might improve cardiovascular function further in combination with this dose of dexmedetomidine, but beneficial effects on anesthesia plane and recovery quality may be lost.

Pneumonia is one of the potential complications of general anaesthesia in horses. Anaesthesia is known to increase neutrophils in bronchoalveolar lavage fluid (BALF) of horses after lateral recumbency, but studies after dorsal recumbency are lacking. Our primary aim was to determine when lung inflammation reaches its maximum and how rapidly BALF cytology returns to baseline after anaesthesia in dorsal recumbency. A secondary aim was to investigate the possible effect of vatinoxan, a novel drug, on the BALF cytology results. Six healthy experimental horses were enrolled in this observational crossover study. The horses were subject to repeated BALF and blood sampling for 7 days after general anaesthesia with two treatment protocols, and without anaesthesia (control). During the two treatments, the horses received either medetomidine-vatinoxan or medetomidine-placebo as premedication, and anaesthesia was induced with ketamine-midazolam and maintained with isoflurane for 1 h in dorsal recumbency. The differences in BALF and blood variables between the two anaesthesia protocols and control were analysed with repeated measures analysis of variance models. In this study, anaesthesia in dorsal recumbency resulted in no clinically relevant changes in airway cytology that could be differentiated from the effect of repeated BALF sampling. No differences in BALF matrix metalloproteinase gelatinolytic activity could be detected between the two treatments or the control series. Marked increase in serum amyloid A was detected in some animals. Vatinoxan as premedication did not consistently affect lung cytology or blood inflammatory markers after anaesthesia.

Objective To determine the effect of intravenous vatinoxan administration on bradycardia, hypertension and level of anaesthesia induced by medetomidine-tiletamine-zolazepam in red deer (Cervus elaphus). Study design and animals A total of 10 healthy red deer were enrolled in a randomized, controlled, experimental, crossover study. Methods Deer were administered a combination of 0.1 mg kg⁻¹ medetomidine hydrochloride and 2.5 mg kg⁻¹ tiletamine-zolazepam intramuscularly, followed by 0.1 mg kg⁻¹ vatinoxan hydrochloride or equivalent volume of saline intravenously (IV) 35 minutes after anaesthetic induction. Heart rate (HR), mean arterial blood pressure (MAP), respiration rate (fR), end-tidal CO2 (PE′CO2), arterial oxygen saturation (SpO2), rectal temperature (RT) and level of anaesthesia were assessed before saline/vatinoxan administration (baseline) and at intervals for 25 minutes thereafter. Differences within treatments (change from baseline) and between treatments were analysed with linear mixed effect models (p < 0.05). Results Maximal (81 ± 10 beats minute⁻¹) HR occurred 90 seconds after vatinoxan injection and remained significantly above baseline (42 ± 4 beats minute⁻¹) for 15 minutes. MAP significantly decreased from baseline (122 ± 10 mmHg) to a minimum MAP of 83 ± 6 mmHg 60 seconds after vatinoxan and remained below baseline until end of anaesthesia. HR remained unchanged from baseline (43 ± 5 beats minute⁻¹) with the saline treatment, while MAP decreased significantly (112 ± 16 mmHg) from baseline after 20 minutes. PE′CO2, fR, and SpO2 showed no significant differences between treatments, while RT decreased significantly 25 minutes after vatinoxan. Level of anaesthesia was not significantly influenced by vatinoxan. Conclusion and clinical relevance Vatinoxan reversed hypertension and bradycardia induced by medetomidine without causing hypotension or affecting the level of anaesthesia in red deer. However, the effect on HR subsided 15 minutes after vatinoxan IV administration. Vatinoxan has the potential to reduce anaesthetic side effects in non-domestic ruminants immobilized with medetomidine-tiletamine-zolazepam.

Objective: To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. Animals: 8 healthy Beagles. Procedures: Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 μg/kg], medetomidine [20 μg/kg] and vatinoxan [400 μg/kg], and medetomidine [40 μg/kg] and vatinoxan [800 μg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments. Results: Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20. Conclusions and clinical relevance: Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.

Objective To investigate the impact of intramuscular (IM) co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. Study design Randomized masked crossover study. Animals A total of eight purpose-bred, 3 year-old Beagle dogs. Methods Each dog was instrumented and administered two treatments, 2 weeks apart: medetomidine (20 μg kg⁻¹) and butorphanol (100 μg kg⁻¹) premedication with vatinoxan (500 μg kg⁻¹; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg⁻¹). Atipamezole (100 μg kg⁻¹) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured and cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analyzed with repeated measures analysis of covariance models. p-values <0.05 were considered statistically significant. Sedation, induction, intubation and recovery scores were assessed. Results At most time points HR and CI were significantly higher and SVRI and CVP significantly lower with MVB than MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than MB; mild hypotension (57–59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. Conclusions and clinical relevance Haemodynamic performance was improved by co-administration of vatinoxan with medetomidine–butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.

Medetomidine is an α-2 adrenoceptor agonist commonly combined with ketamine for immobilization of nondomestic mammals. However, it may cause some remarkable adverse effects such as bradycardia, hypertension, and hypoxemia. Vatinoxan (previously called MK-467 and L-659,066) is an α-2 adrenoceptor antagonist that affects mostly the peripheral receptors due to its minimal ability to cross the blood-brain barrier. Therefore it alleviates the peripheral cardiovascular and pulmonary effects of medetomidine while sedation is maintained. In this study, the hypothesis was that vatinoxan would dose-dependently alleviate medetomidineinduced bradycardia, hypertension, and hypoxemia when administered intravenously (IV) after medetomidine and ketamine were administered intramuscularly (IM) to markhors (Capra falconeri heptneri), without impairing the immobilization. Various doses of vatinoxan were studied. In this prospective, randomized, assessor-blinded, clinical crossover study, eight markhors were immobilized two times (16 paired immobilizations altogether) with medetomidine (80 μg/kg) and ketamine (1.5 mg/kg), according to the estimated weight, IM in the same dart. Approximately 19 min later, vatinoxan (117-297 μg/kg) or saline placebo was injected IV. Atipamezole was used as a reversal agent. Pulse and respiratory rates, indirect blood pressures, arterial oxygen saturation, and body temperature were measured and blood samples collected. In general, vatinoxan alleviated the hypertension induced by medetomidine without affecting the quality of immobilization. The dose of vatinoxan correlated significantly with the reduction in arterial blood pressure. Vatinoxan showed potential to enhance cardiovascular function in captive nondomestic small ruminants immobilized with medetomidine-ketamine.

A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7 μg/kg IV alone (MED) or with vatinoxan hydrochloride 140 μg/kg IV (MED + V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60 min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24 h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied. Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED + V (P = 0.018). Cardiac index (CI) and oxygen delivery index (DO2I) decreased significantly more with MED, with the largest difference observed at 20 min: CI was 39 ± 2 and 73 ± 18 (P = 0.009) and DO2I 7.4 ± 1.2 and 15.3 ± 4.8 (P = 0.014) mL/min/kg with MED and MED + V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED + V.

Objective: To quantify the peripheral selectivity of vatinoxan (L-659,066, MK-467) in dogs by comparing the concentrations of vatinoxan, dexmedetomidine and levomedetomidine in plasma and central nervous system (CNS) tissue after intravenous (IV) coadministration of vatinoxan and medetomidine. Study design: Experimental, observational study. Animals: A group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 ± 0.1 years (mean ± standard deviation). Methods: All dogs were administered a combination of medetomidine (40 μg kg-1) and vatinoxan (800 μg kg-1) as IV bolus. After 20 minutes, the dogs were euthanized with an IV overdose of pentobarbital (140 mg kg-1) and both venous plasma and CNS tissues (brain, cervical and lumbar spinal cord) were harvested. Concentrations of dexmedetomidine, levomedetomidine and vatinoxan in all samples were quantified by liquid chromatography-tandem mass spectrometry and data were analyzed with nonparametric tests with post hoc corrections where appropriate. Results: All dogs became deeply sedated after the treatment. The CNS-to-plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dexmedetomidine and levomedetomidine in the CNS were three- to seven-fold of those in plasma. Conclusions and clinical relevance: With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when coadministered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.

Background Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2‐adrenoceptors. Vatinoxan, a peripheral α2‐antagonist, has been shown experimentally to alleviate the adverse effects of some α2‐agonists in horses. However, vatinoxan has not been investigated during constant‐rate infusion (CRI) of medetomidine in standing horses. Objectives To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility, and on sedation level during CRI of medetomidine. Study design Experimental, randomised, blinded, cross‐over study. Methods Six healthy horses were given medetomidine hydrochloride, 7 μg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 μg/kg i.v., followed by CRI of medetomidine at 3.5 μg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t‐tests as appropriate. Results Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared to MED+V. For example, at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001), respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). Main limitations Experimental study with healthy, unstimulated animals. Conclusions Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min. This article is protected by copyright. All rights reserved.

To compare the effects of pretreatment with dexamethasone, physical stress (exercise), or both on sedation and plasma hormone and glucose concentrations in dogs treated with dexmedetomidine (DEX). 6 healthy purpose-bred Beagles. Dogs received 4 treatments each in a randomized order prior to i.v. administration of DEX (5 fLg/kg). Pretreatments were as follows: (1) i.v. administration of saline (0.9% NaCI) solution and no exercise (control group); (2) IV administration of dexamethasone (0.05 mg/kg) and no exercise (DM group); (3) i.v. administration of saline solution and exercise (EX group; 15 minutes of trotting on a treadmill at a speed of 2 m/s); and (4) i.v. administration of dexamethasone and exercise (DM+EX group). Following DEX administration, all dogs had similar times to recumbency and sedation index values, irrespective of pretreatment with values, irrespective of pretreatment with dexam-d ethasone or exercise. Plasma catecholamine concentrations decreased after DEX administration. Compared with control group dogs, plasma cortisol concentrations were higher in EX-group dogs prior to DEX administration and lower in DM- and DM+EX-group dogs following DEX administration. Administration of DEX decreased plasma cortisol concentration in EX-group dogs only. Plasma glucose concentration was not influenced by exercise or dexamethasone administration was lower than baseline concentrations at 30 minutes after DEX administration and returned to baseline values by 90 minutes. Heart and respiratory rates and rectal temperature increased during exercise. After DEX administration, these values decreased below baseline values. The decrease in heart rate was of shorter duration in dogs that underwent pretreatment with dexamethasone, exercise, or both than in control group dogs. Pretreatment with dexamethasone, moderate physical stress (exercise), or both did not influence sedation or cause adverse effects in healthy dogs treated with DEX.

To investigate heart rate characteristics in dogs undergoing ovariohysterectomy following premedication with medetomidine or acepromazine. Clinical trial. 43 client-owned dogs. 24-hour ambulatory electrocardiography was performed beginning approximately 1 hour prior to administration of premedications. Dogs were premedicated with medetomidine and butorphanol (n = 21) or acepromazine and butorphanol (22) and, approximately 85 minutes later, were anesthetized with propofol and isoflurane. Electrocardiographic recordings were examined to determine heart rate, cardiac conduction disturbances (ventricular premature complexes and atrioventricular block), and indices of heart rate variability (HRV). Minimum heart rate during the 24-hour recording period was significantly lower among dogs given medetomidine than among dogs given acepromazine, but during the postoperative period, heart rate increased in all dogs as they became physically active. Intraoperative time domain HRV indices were lower and the low frequency-to-high frequency ratio was higher among dogs given acepromazine than among dogs given medetomidine; however, significant differences between groups were no longer seen by 6 hours after surgery. There was no significant difference between groups with regard to the number of ventricular premature complexes or to values of scaling exponent alpha2 (a nonlinear measure of HRV). Results suggest that there are greater enhancements in vagally related heart rate indices in medetomidine-treated dogs that may persist until 6 hours after surgery. Despite the low heart rates, dogs given medetomidine showed expected responses to surgery and positional stimuli, and the 2 preanesthetic protocols may not result in different prevalences of ventricular premature complexes.

The effects of propofol infusion were compared with propofol/isoflurane anaesthesia in six beagles premedicated with 10 microg/kg intramuscular (i.m.) dexmedetomidine. The suitability of a cold pressor test (CPT) as a stress stimulus in dogs was also studied. Each dog received isoflurane (end tidal 1.0%, induction with propofol) with and without CPT; propofol (200 microg/kg/min, induction with propofol) with and without CPT; premedication alone with and without CPT in a randomized block study in six separate sessions. Heart rate and arterial blood pressures and gases were monitored. Plasma catecholamine, beta-endorphin and cortisol concentrations were measured. Recovery profile was observed. Blood pressures stayed within normal reference range but the dogs were bradycardic (mean heart rate < 70 bpm). PaCO2 concentration during anaesthesia was higher in the propofol group (mean > 57 mmHg) when compared with isoflurane (mean < 52 mmHg). Recovery times were longer with propofol than when compared with the other treatments. The mean extubation times were 8 +/- 3.4 and 23 +/- 6.3 min after propofol/isoflurane and propofol anaesthesia, respectively. The endocrine stress response was similar in all treatments except for lower adrenaline level after propofol infusion at the end of the recovery period. Cold pressor test produced variable responses and was not a reliable stress stimulus in the present study. Propofol/isoflurane anaesthesia was considered more useful than propofol infusion because of milder degree of respiratory depression and faster recovery.