Alpha2 Antagonist Vatinoxan Does Not Abolish the Preconditioning Effect of Dexmedetomidine on Experimental Ischaemia-Reperfusion Injury in the Equine Small Intestine.
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 alpha2 adrenoreceptor activity. Therefore, the aim of this study was to determine the effect of dexmedetomidine preconditioning with and without the administration of the peripheral alpha2 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 alpha2 adrenoreceptors did not negatively affect dexmedetomidine preconditioning.
Publication Date: 2023-08-30 PubMed ID: 37685019PubMed Central: PMC10486550DOI: 10.3390/ani13172755Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research study aimed to understand whether the alpha-2 antagonist, Vatinoxan, impacts the protective effects of Dexmedetomidine on intestinal injury in horses caused by ischaemia-reperfusion. Results suggest that Vatinoxan does not negate Dexmedetomidine’s protective preconditioning effects.
Study Design and Method
- Twelve horses were involved in this controlled experiment, separated equally into two groups, each assigned a different treatment regimen.
- The first group (referred to as group Dex) received an initial dose of Dexmedetomidine, followed by continuous rate infusion (CRI), while the second group (group DexV) received Vatinoxan along with Dexmedetomidine as a bolus and in CRI form.
- Each horse was then subjected to a median laparotomy, a surgical procedure performed under general anesthesia. A jejunal ischaemia was applied for 90 minutes, stimulating a brief period of reduced blood supply to the intestine, followed by 30 minutes of reperfusion where blood flow was reestablished.
Analysis of Mucosal Damage
- To evaluate the extent of intestine injury caused by ischaemia-reperfusion, full thickness biopsy samples were taken from the horses’ jejuna and analyzed.
- Mucosal damage was assessed by a semi-quantitative injury score and observing apoptotic (cell death) counts via staining for cleaved caspase-3 and TUNEL, two methods used for detecting apoptosis.
- The researchers applied non-parametric tests to compare differences between group Dex and DexV at different time points.
Results and Interpretation
- During the pre-ischaemia and ischaemia phases, no discernible difference in mucosal damage was observed between the two groups.
- However, after the reperfusion phase, group DexV exhibited significantly lower mucosal injury scores compared to group Dex.
- Interestingly, even as DexV showed less mucosal damage, no differences in apoptotic cell counts were found between the two groups.
- The findings suggest that blocking the peripheral alpha adrenoreceptors with Vatinoxan did not negatively affect the Dexmedetomidine’s protective preconditioning effect on ischaemia-reperfusion injury. This conclusion strengthens the understanding that Dexmedetomidine’s beneficial properties may not primarily be influenced by peripheral alpha adrenoreceptors, a previously hypothesized mechanism.
Cite This Article
APA
Verhaar N, Kopp V, Pfarrer C, Neudeck S, König K, Rohn K, Kästner S.
(2023).
Alpha2 Antagonist Vatinoxan Does Not Abolish the Preconditioning Effect of Dexmedetomidine on Experimental Ischaemia-Reperfusion Injury in the Equine Small Intestine.
Animals (Basel), 13(17).
https://doi.org/10.3390/ani13172755 Publication
Researcher Affiliations
- Clinic for Horses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Clinic for Horses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Institute for Anatomy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Small Animal Clinic, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Clinic for Horses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Department of Biometry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Clinic for Horses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
- Small Animal Clinic, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
Grant Funding
- 491094227 / Deutsche Forschungsgemeinschaft
- NA / University of Veterinary Medicine Hannover, Foundation
Conflict of Interest Statement
The authors declare no conflict of interest.
References
This article includes 32 references
- Krenz M, Baines C, Kalogeris T, Korthuis R. Cell Survival Programs and Ischemia/Reperfusion: Hormesis, Preconditioning, and Cardioprotection. Morgan & Claypool Life Sciences; San Rafael, CA, USA: 2013. (Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease).
- Verhaar N, Pfarrer C, Neudeck S, Konig K, Rohn K, Twele L, Kastner S. Preconditioning with lidocaine and xylazine in experimental equine jejunal ischaemia. Equine Vet. J. 2020;53:125–133.
- Konig K.S, Verhaar N, Hopster K, Pfarrer C, Neudeck S, Rohn K, Kastner S.B. Ischaemic preconditioning and pharmacological preconditioning with dexmedetomidine in an equine model of small intestinal ischaemia-reperfusion. PLoS ONE 2020;15:e0224720.
- VanderBroek A.R, Engiles J.B, Kastner S.B, Kopp V, Verhaar N, Hopster K. Protective effects of dexmedetomidine on small intestinal ischaemia-reperfusion injury in horses. Equine Vet. J. 2020;53:569–578.
- Sun Y, Gao Q, Wu N, Li S.D, Yao J.X, Fan W.J. Protective effects of dexmedetomidine on intestinal ischemia-reperfusion injury. Exp. Ther. Med. 2015;10:647–652.
- Kilic K, Hanci V, Selek S, Sozmen M, Kilic N, Citil M, Yurtlu D.A, Yurtlu B.S. The effects of dexmedetomidine on mesenteric arterial occlusion-associated gut ischemia and reperfusion-induced gut and kidney injury in rabbits. J. Surg. Res. 2012;178:223–232.
- Yang J, Wu Y, Xu Y, Jia J, Xi W, Deng H, Tu W. Dexmedetomidine Resists Intestinal Ischemia-Reperfusion Injury by Inhibiting TLR4/MyD88/NF-κB Signaling. J. Surg. Res. 2021;260:350–358.
- Zhang Q, Liu X.M, Hu Q, Liu Z.R, Liu Z.Y, Zhang H.G, Huang Y.L, Chen Q.H, Wang W.X, Zhang X.K. Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway. J. Transl. Med. 2021;19:463.
- Liu X.M, Chen Q.H, Hu Q, Liu Z, Wu Q, Liang S.S, Zhang H.G, Zhang Q, Zhang X.K. Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades. Exp. Mol. Pathol. 2020;115:104444.
- Doze V.A, Chen B.X, Maze M. Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology 1989;71:75–79.
- Bettschart-Wolfensberger R, Freeman S, Bowen I, Aliabadi F, Weller R, Huhtinen M, Clarke K. Cardiopulmonary effects and pharmacokinetics of iv dexmedetomidine in ponies. Equine Vet. J. 2005;37:60–64.
- Hieble J.P, Ruffolo R.R. Jr. Possible structural and functional relationships between imidazoline receptors and α2-adrenoceptors. Ann. N. Y. Acad. Sci. 1995;763:8–21.
- Zhang X.Y, Liu Z.M, Wen S.H, Li Y.S, Li Y, Yao X, Huang W.Q, Liu K.X. Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology 2012;116:1035–1046.
- Clineschmidt B.V, Pettibone D.J, Lotti V.J, Hucker H.B, Sweeney B.M, Reiss D.R, Lis E.V, Huff J.R, Vacca J. 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, Ekiri A, Scheinin M, Taylor P.M, Vainio O.M. Clinical effects and pharmacokinetic variables of romifidine and the peripheral α2-adrenoceptor antagonist MK-467 in horses. Vet. Anaesth. Analg. 2016;43:599–610.
- Pakkanen S.A, Raekallio M.R, Mykkanen A.K, Salla K.M, de Vries A, Vuorilehto L, Scheinin M, Vainio O.M. 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.
- Vainionpaa M.H, Raekallio M.R, Pakkanen S.A, Ranta-Panula V, Rinne V.M, Scheinin M, Vainio O.M. 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.
- Tapio H.A, Raekallio M.R, Mykkanen A.K, Al-Ramahi D, Scheinin M, Hautajarvi H.J, Mannikko S, Vainio O. Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine. Vet. J. 2019;251:105345.
- Wittenberg-Voges L, Kastner S.B, Raekallio M, Vainio O.M, Rohn K, Hopster K. Effect of dexmedetomidine and xylazine followed by MK-467 on gastrointestinal microperfusion in anaesthetized horses. Vet. Anaesth. Analg. 2018;45:165–174.
- Krug A. Mikrozirkulation und sauerstoffversorgung des gewebes. Phlebologie 2006;35:300–312.
- Neudeck S, Twele L, Kopp V, Kastner S. Pharmacodynamics and plasma concentrations of dexmedetomidine with or without vatinoxan as a constant-rate infusion in horses anaesthetized with isoflurane—A pilot study. J. Vet. Pharmacol. Ther. 2021;44:754–765.
- Chiu C.-J, McArdle A.H, Brown R, Scott H.J, Gurd F.N. Intestinal mucosal lesion in low-flow states: I. A morphological, hemodynamic, and metabolic reappraisal. Arch. Surg. 1970;101:478–483.
- White N, Moore J, Trim C. Mucosal alterations in experimentally induced small intestinal strangulation obstruction in ponies. Am. J. Vet. Res. 1980;41:193–198.
- Kamibayashi T, Hayashi Y, Mammoto T, Yamatodani A, Sumikawa K, Yoshiya I. Role of the vagus nerve in the antidysrhythmic effect of dexmedetomidine on halothane/epinephrine dysrhythmias in dogs. Anesthesiology 1995;83:992–999.
- Hector R.C, Rezende M.L, Nelson B.B, Monnet E. Cardiopulmonary function and intestinal blood flow in anaesthetised, experimentally endotoxaemic horses given a constant rate infusion of dexmedetomidine. Equine Vet. J. 2022;54:820–828.
- Hernandez G, Tapia P, Alegria L, Soto D, Luengo C, Gomez J, Jarufe N, Achurra P, Rebolledo R, Bruhn A. Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock. Crit. Care 2016;20:234.
- Restitutti F, Laitinen M.R, Raekallio M.R, Vainionpaa M, T O'Brien R, Kuusela E, Vainio O.M. Effect of MK-467 on organ blood flow parameters detected by contrast-enhanced ultrasound in dogs treated with dexmedetomidine. Vet. Anaesth. Analg. 2013;40:e48–e56.
- Dancker C, Hopster K, Rohn K, Kastner S.B. Effects of dobutamine, dopamine, phenylephrine and noradrenaline on systemic haemodynamics and intestinal perfusion in isoflurane anaesthetised horses. Equine Vet. J. 2018;50:104–110.
- Gao H, Chen L, Yang H.T. Activation of α1B-adrenoceptors alleviates ischemia/reperfusion injury by limitation of mitochondrial Ca2+ overload in cardiomyocytes. Cardiovasc. Res. 2007;75:584–595.
- Kariya T, Minatoguchi S, Ohno T, Yamashita K, Uno Y, Arai M, Koshiji M, Fujiwara T, Fujiwara H. Infarct size-reducing effect of ischemic preconditioning is related to alpha1b-adrenoceptors but not to alpha1a-adrenoceptors in rabbits. J. Cardiovasc. Pharmacol. 1997;30:437–445.
- Liu C, Shen Z, Liu Y, Peng J, Miao L, Zeng W, Li Y. Sevoflurane protects against intestinal ischemia-reperfusion injury partly by phosphatidylinositol 3 kinases/Akt pathway in rats. Surgery 2015;157:924–933.
- Redfors B, Oras J, Shao Y, Seemann-Lodding H, Ricksten S.E, Omerovic E. Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo). Int. J. Cardiol. 2014;176:815–821.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
