Effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole

Abstract

OBJECTIVE To evaluate effects of the peripherally acting α-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

Cardiovascular effects of intravenous vatinoxan in wild boars (Sus scrofa) anaesthetised with intramuscular medetomidine‐tiletamine‐zolazepam

“…18 It has been demonstrated in many species sedated with (dex)medetomidine that the duration of cardiovascular effects of VTX can be dose-dependent. 9,13,17,25,27 Therefore, the short effect of VTX on HR might be attributed to the low VTX dose, or the dose ratio between the alpha-2-adrenergic agonist and antagonist in the current study. 25,28 However, comparable doses in horses (0.15 mg kg −1 IV), administered 10 min after detomidine (0.02 mg/kg IV), led to an increase in HR that was sustained for 90 min after VTX administration.…”

“…39 Studies in sheep and dogs showed lower haemoglobin concentrations when the alpha-2-adrenergic agonist was combined with VTX. 12,13,41 All animals showed a sufficient level plane of anaesthesia, and no difference was detected between treatments. However, the additional anaesthetic effects of tiletamine and zolazepam used in the study does not allow interpretation of the impact of VTX on the level or duration of the medetomidine-induced sedation.…”

“…Previous studies have shown the potential of the peripheral alpha-2-adrenergic antagonist vatinoxan to minimize cardiovascular side effects of alpha-2-adrenergic agonists without affecting sedation, for example, in dogs and sheep. [8][9][10][11][12][13] Vatinoxan improved cardiac output, decreased systemic vascular resistance and thereby improved tissue oxygen delivery in dogs, horses and cats. 9,10,[14][15][16] The effects of vatinoxan have been primarily investigated in domestic species.…”

Effects of vatinoxan on xylazine‐induced pulmonary alterations in sheep

“…This concept has been well‐documented in various species (Honkavaara et al, 2011; Restitutti et al, 2012; Rolfe et al, 2012; Sainmaa et al, 2019; Siao et al, 2017; de Vires et al, 2016), including sheep (Adam, Huuskonen, et al, 2018; Adam, Raekallio, Keskitalo, et al, 2018; Adam, Raekallio, Salla, et al, 2018; Bryant et al, 1998; Raekallio et al, 2010). Moreover, vatinoxan has no appreciable impact on agonist‐induced sedation in many species (Adam, Raekallio, Keskitalo, et al, 2018; Adam, Raekallio, Salla, et al, 2018; Honkavaara Pypendop et al, 2017; Honkavaara et al, 2008, 2017; Raekallio et al, 2010; Restitutti et al, 2011; Siao et al, 2017; Tapio et al, 2018; Vainionpää et al, 2013; de Vries et al, 2016), nor has it shown antinociceptive effects when the agonist concentration is similar in plasma (Huuskonen et al, 2020). Recently, we demonstrated in sheep that premedication with vatinoxan alleviated dexmedetomidine‐induced bronchoconstriction and hypoxaemia, and prevented the opacity detected by computer tomography (CT) in the ventrolateral parts of lungs (Adam, Huuskonen, et al, 2018).…”

Tendencies and perspectives of central alpha2-adrenomimetic application in medicobiological research

“…According to the results of many studies, it was found that a decrease in cardiac output is not associated with a direct effect of α2-AM on myocardial contractility. It is secondary to an increase of total peripheral vascular resistance and a decrease in heart rate (HR) [25].…”