Alpha(2) Antagonist Vatinoxan Does Not Abolish the Preconditioning Effect of Dexmedetomidine on Experimental Ischaemia–Reperfusion Injury in the Equine Small Intestine

SIMPLE SUMMARY: Intestinal disease with disruption of blood flow (ischaemia) is associated with a relatively high mortality rate in horses. Many investigations have focused on treatment strategies that reduce tissue injury. The sedative drug dexmedetomidine was found to precondition intestines subjected to ischaemia, resulting in reduced injury in different species, including horses. However, it remains unknown what exactly mediates this effect. Therefore, the aim of this study was to determine the effect of dexmedetomidine preconditioning with and without the administration of a drug called vatinoxan, which antagonizes the action of dexmedetomidine on the peripheral alpha(2) adrenoreceptor. In 12 horses under general anaesthesia, intestinal ischaemia was implemented, followed by tissue reperfusion. Six horses received dexmedetomidine only (group Dex), while the other six horses received both dexmedetomidine and vatinoxan (DexV). Intestinal samples were taken to evaluate the degree of tissue injury, followed by a comparison between the groups. There was no difference before and directly after the disruption of tissue blood flow. After reperfusion, group DexV showed less mucosal injury compared to group Dex. There were no significant differences in programmed cell death between the treatment groups. In conclusion, antagonizing the peripheral alpha(2) adrenoreceptors did not negatively affect dexmedetomidine preconditioning. ABSTRACT: Pharmacological preconditioning with dexmedetomidine has been shown to ameliorate intestinal ischaemia reperfusion injury in different species, including horses. However, it remains unknown if this effect is related to alpha(2) adrenoreceptor activity. Therefore, the aim of this study was to determine the effect of dexmedetomidine preconditioning with and without the administration of the peripheral alpha(2) antagonist vatinoxan. This prospective randomized experimental trial included 12 horses equally divided between two treatment groups. Horses in group Dex received a bolus of dexmedetomidine followed by a continuous rate infusion (CRI), while group DexV additionally received vatinoxan as bolus and CRI. A median laparotomy was performed under general anaesthesia, and jejunal ischaemia was applied for 90 min, followed by 30 min of reperfusion. Mucosal damage was evaluated in full thickness biopsies by use of a semiquantitative mucosal injury score and by determining the apoptotic cell counts with immunohistochemical staining for cleaved caspase-3 and TUNEL. Comparisons between the groups and time points were performed using non-parametric tests (p < 0.05). During pre-ischaemia and ischaemia, no differences could be found in mucosal injury between the groups. After reperfusion, group DexV showed lower mucosal injury scores compared to group Dex. The apoptotic cell counts did not differ between the groups. In conclusion, antagonizing the peripheral alpha(2) adrenoreceptors did not negatively affect dexmedetomidine preconditioning.