Effect of dexmedetomidine and xylazine followed by MK-467 on gastrointestinal microperfusion in anaesthetized horses

Published:September 15, 2017DOI:



      To compare the effects of MK-467 during isoflurane anaesthesia combined with xylazine or dexmedetomidine on global and gastrointestinal perfusion parameters.

      Study design

      Prospective, randomized experimental trial.


      A total of 15 warmblood horses.


      Horses were divided into two groups for administration of either dexmedetomidine (D) or xylazine (X) for premedication (D: 3.5 μg kg−1; X: 0.5 mg kg−1) and as constant rate infusion during isoflurane anaesthesia (D: 7 μg kg−1 hour−1; X: 1 mg kg−1 hour−1). During anaesthesia, heart rate, mean arterial blood pressure (MAP), systemic vascular resistance index (SVRI) and cardiac index (CI) were measured. Microperfusion of the colon, jejunum and stomach was measured using laser Doppler flowmetry. After 2 hours of stabilization, MK-467 (250 μg kg−1) was administered, and measurements were continued for another 90 minutes. For statistical analysis, the permutation test and Wilcoxon rank-sum test were used (p < 0.05).


      There were no differences in baseline measurements between groups. The MK-467 bolus resulted in a significant decrease in MAP (D: –58%; X: –48%) and SVRI (D: –68%; X: –65%) lasting longer in group D (90 minutes) compared to group X (60 minutes). While CI increased (D: +31%; X: +35%), microperfusion was reduced in the colon (D: –44%; X: –34%), jejunum (D: –26%; X: –33%) and stomach (D: –37%; X: –35%).

      Conclusions and clinical relevance

      Alpha-2-agonist induced vasoconstriction was reversed by the MK-467 dose used, resulting in hypotension and rise in CI. Gastrointestinal microperfusion decreased, probably as a result of insufficient perfusion pressure. An infusion rate for MK-467 as well as an ideal agonist/antagonist ratio should be determined.


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        • Asano Y.
        • Koehler R.C.
        • Kawaguchi T.
        • et al.
        Pial arteriolar constriction to alpha 2-adrenergic agonist dexmedetomidine in the rat.
        Am J Physiol. 1997; 272: H2547-2556
        • Bettschart-Wolfensberger R.
        • Freeman S.L.
        • Bowen I.M.
        • et al.
        Cardiopulmonary effects and pharmacokinetics of i.v. dexmedetomidine in ponies.
        Equine Vet J. 2005; 37: 60-64
        • Branson K.R.
        • Benson G.J.
        • Thurmon J.C.
        • et al.
        Hemodynamic parameters and tissue oxygenation during halothane anesthesia in normal horses and those experiencing post anesthetic lameness.
        J Equine Vet Sci. 1992; 12: 153-159
        • Bryant C.E.
        • Thompson J.
        • Clarke K.W.
        Characterisation of the cardiovascular pharmacology of medetomidine in the horse and sheep.
        Res Vet Sci. 1998; 65: 149-154
        • Chatterjee K.
        • Parmley W.W.
        • Swan H.J.
        • et al.
        Beneficial effects of vasodilator agents in severe mitral regurgitation due to dysfunction of subvalvar apparatus.
        Circulation. 1973; 48: 684-690
        • Clineschmidt B.V.
        • Pettibone D.J.
        • Lotti V.J.
        • et al.
        A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066.
        J Pharmacol Exp Ther. 1988; 245: 32-40
        • de Vries A.
        • Pakkanen S.A.
        • Raekallio M.R.
        • et al.
        Clinical effects and pharmacokinetic variables of romifidine and the peripheral alpha 2-adrenoceptor antagonist MK-467 in horses.
        Vet Anaesth Analg. 2016; 43: 599-610
        • Edner A.
        • Nyman G.
        • Essén-Gustavsson B.
        The relationship of muscle perfusion and metabolism with cardiovascular variables before and after detomidine injection during propofol–ketamine anaesthesia in horses.
        Vet Anaesth Analg. 2002; 29: 182-199
        • Ernsberger P.
        • Meeley M.P.
        • Mann J.J.
        • et al.
        Clonidine binds to imidazole binding sites as well as α2-adrenoceptors in the ventrolateral medulla.
        Eur J Pharmacol. 1987; 134: 1-13
        • Gozalo-Marcilla M.
        • Gasthuys F.
        • Schauvliege S.
        Partial intravenous anaesthesia in the horse: a review of intravenous agents used to supplement equine inhalation anaesthesia. Part 2: opioids and alpha-2 adrenoceptor agonists.
        Vet Anaesth Analg. 2014; 2 (12196)
        • Gozalo-Marcilla M.
        • Hopster K.
        • Gasthuys F.
        • et al.
        Effects of a constant-rate infusion of dexmedetomidine on the minimal alveolar concentration of sevoflurane in ponies.
        Equine Vet J. 2013; 45: 204-208
        • Grum C.M.
        Tissue oxygenation in low flow states and during hypoxemia.
        Crit Care Med. 1993; 21: S44-S49
        • Grum C.M.
        • Fiddian-Green R.G.
        • Pittenger G.L.
        • et al.
        Adequacy of tissue oxygenation in intact dog intestine.
        J Appl Physiol Respir Environ Exerc Physiol. 1984; 56: 1065-1069
        • Honkavaara J.
        • Restitutti F.
        • Raekallio M.
        • et al.
        Influence of MK-467, a peripherally acting alpha2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs.
        Drug Metab Dispos. 2012; 40: 445-449
        • Honkavaara J.M.
        • Restitutti F.
        • Raekallio M.R.
        • et al.
        The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.
        J Vet Pharmacol Ther. 2011; 34: 332-337
        • Hopster K.
        • Hopster-Iversen C.
        • Geburek F.
        • et al.
        Temporal and concentration effects of isoflurane anaesthesia on intestinal tissue oxygenation and perfusion in horses.
        Vet J. 2015; 205: 62-68
        • Hopster K.
        • Wogatzki A.
        • Conze P.
        • et al.
        Effects of positive end-expiratory pressure titration on intestinal oxygenation and perfusion in isoflurane anaesthetised horses.
        Equine Vet J. 2016; 49: 250-256
        • Hubbell J.A.
        • Muir W.W.
        Antagonism of detomidine sedation in the horse using intravenous tolazoline or atipamezole.
        Equine Vet J. 2006; 38: 238-241
        • Kaartinen J.
        • del Castillo J.R.
        • Salla K.
        • et al.
        Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs.
        Vet J. 2014; 202: 353-360
        • Langer S.Z.
        • Shepperson N.B.
        Postjunctional alpha 1-adrenoceptors: preferential innervation of alpha 1-adrenoceptors and the role of neuronal uptake.
        J Cardiovasc Pharmacol. 1982; 4: S8-13
        • Marcilla M.G.
        • Schauvliege S.
        • Duchateau L.
        • et al.
        Cardiopulmonary effects of two constant rate infusions of dexmedetomidine in isoflurane anaesthetized ponies.
        Vet Anaesth Analg. 2010; 37: 311-321
        • Mueller C.
        • Hopster K.
        • Hopster-Iversen C.
        • et al.
        Elaboration of a xylazine and dexmedetomidine infusion regime which provides a constant level of sedation in horses.
        Pferdeheilkunde. 2012; 28: 668-674
        • Neviere R.
        • Chagnon J.L.
        • Teboul J.L.
        • et al.
        Small intestine intramucosal PCO(2) and microvascular blood flow during hypoxic and ischemic hypoxia.
        Crit Care Med. 2002; 30: 379-384
        • Ostman M.
        • Biber B.
        • Martner J.
        • et al.
        Effects of isoflurane on vascular tone and circulatory autoregulation in the feline small intestine.
        Acta Anaesthesiol Scand. 1985; 29: 389-394
        • Pagel P.S.
        • Proctor L.T.
        • Devcic A.
        • et al.
        A novel alpha 2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs.
        J Cardiothorac Vasc Anesth. 1998; 12: 429-434
        • Pakkanen S.A.
        • Raekallio M.R.
        • Mykkanen A.K.
        • et al.
        Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane.
        Vet Anaesth Analg. 2015; 42: 527-536
        • Poppel N.
        • Hopster K.
        • Geburek F.
        • et al.
        Influence of ketamine or xylazine supplementation on isoflurane anaesthetized horses—a controlled clinical trial.
        Vet Anaesth Analg. 2015; 42: 30-38
        • Reichert C.
        • Kastner S.B.
        • Hopster K.
        • et al.
        Use of micro-lightguide spectrophotometry for evaluation of microcirculation in the small and large intestines of horses without gastrointestinal disease.
        Am J Vet Res. 2014; 75: 990-996
        • Savola J.M.
        Cardiovascular actions of medetomidine and their reversal by atipamezole.
        Acta Vet Scand Suppl. 1989; 85: 39-47
        • Savola J.M.
        • Virtanen R.
        Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine.
        Eur J Pharmacol. 1991; 195: 193-199
        • Serteyn D.
        • Lavergne L.
        • Coppens P.
        • et al.
        Equine post anaesthetic myositis: muscular post ischaemic hyperaemia measured by laser Doppler flowmetry.
        Vet Rec. 1988; 123: 126-128
        • Steffey E.P.
        • Pascoe P.J.
        • Woliner M.J.
        • et al.
        Effects of xylazine hydrochloride during isoflurane-induced anesthesia in horses.
        Am J Vet Res. 2000; 61: 1225-1231
        • Talke P.O.
        • Traber D.L.
        • Richardson C.A.
        • et al.
        The effect of α2 agonist-induced sedation and its reversal with an α2 antagonist on organ blood flow in sheep.
        Anesth Analg. 2000; 90: 1060-1066
        • Vainionpaa M.H.
        • Raekallio M.R.
        • Pakkanen S.A.
        • et al.
        Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.
        Vet Anaesth Analg. 2013; 40: 257-264
        • van Zwieten P.A.
        • Timmermans P.B.
        • Thoolen M.J.
        • et al.
        Inhibitory effect of calcium antagonist drugs on vasoconstriction induced by vascular alpha 2-adrenoceptor stimulation.
        Am J Cardiol. 1986; 57: 11D-15D
        • Virtanen R.
        • Savola J.M.
        • Saano V.
        • et al.
        Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist.
        Eur J Pharmacol. 1988; 150: 9-14
        • Wagner A.E.
        • Hellyer P.W.
        Survey of anesthesia techniques and concerns in private veterinary practice.
        J Am Vet Med Assoc. 2000; 217: 1652-1657
        • Yamashita K.
        • Tsubakishita S.
        • Futaok S.
        • et al.
        Cardiovascular effects of medetomidine, detomidine and xylazine in horses.
        J Vet Med Sci. 2000; 62: 1025-1032