Skip to main content

Intraperitoneal co-administration of low dose urethane with xylazine and ketamine for extended duration of surgical anesthesia in rats


Procedures involving complex surgical techniques in rats, such as placement of abdominal aortic graft require extended duration of surgical anesthesia, which often can be achieved by repeated administrations of xylazine-ketamine combination. However such repeated anesthetic administration, in addition to being technically challenging, may be associated with potential adverse events due to cumulative effects of anesthesia. We report here the feasibility of using urethane at low dose (1/10 the recommended anesthetic dose) in combination with a xylazine-ketamine mix to achieve an extended duration of surgical anesthesia in rats. The anesthesia induction phase was quick and smooth with an optimal phase of surgical anesthesia achieved for up to 90 minutes, which was significantly higher compared to that achieved with use of only xylazine-ketamine combination. The rectal temperature, heart rate and respiratory rate were within the physiological range with an uneventful recovery phase. Post surgery the rats were followed up to 3 months without any evidence of tumor or any other adverse effects related to the use of the urethane anesthetic combination. We conclude that low dose urethane can be effectively used in combination with xylazine and ketamine to achieve extended duration of surgical anesthesia up to 90 minutes in rats.


  1. 1.

    Arun KH, Kaul CL, Ramarao P. AT1 receptors and L-type calcium channels: functional coupling in supersensitivity to angiotensin II in diabetic rats. Cardiovasc Res 2005; 65(2): 374–386.

    Article  CAS  Google Scholar 

  2. 2.

    Arun KH, Kaul CL, Poduri R. Tempol augments angiotensin IIinduced AT2 receptor-mediated relaxation in diabetic rat thoracic aorta. J Hypertens 2004; 22(11): 2143–2152.

    Article  CAS  Google Scholar 

  3. 3.

    Piche M, Watanabe N, Hotta H. Regulation of gastric motility and blood flow during acute nociceptive stimulation of the paraspinal muscles in urethane-anaesthetised rats. J Physiol Sci 2014; 64(1): 37–46.

    Article  CAS  Google Scholar 

  4. 4.

    Habara H, Hayashi Y, Inomata N, Niijima A, Kangawa K. Organspecific activation of the gastric branch of the efferent vagus nerve by ghrelin in urethane-anesthetized rats. J Pharmacol Sci 2014; 124(1): 31–39.

    Article  CAS  Google Scholar 

  5. 5.

    Tran RT, Choy WM, Cao H, Qattan I, Chiao JC, Ip WY, Yeung KW, Yang J. Fabrication and characterization of biomimetic multichanneled crosslinked-urethane-doped polyester tissue engineered nerve guides. J Biomed Mater Res A 2014; 102(8): 2793–2804.

    Article  CAS  Google Scholar 

  6. 6.

    Krynauw H, Bruchmuller L, Bezuidenhout D, Zilla P, Franz T. Degradation-induced changes of mechanical properties of an electro-spun polyester-urethane scaffold for soft tissue regeneration. J Biomed Mater Res B Appl Biomater 2011; 99(2): 359–368.

    Article  CAS  Google Scholar 

  7. 7.

    Chiono V, Sartori S, Rechichi A, Tonda-Turo C, Vozzi G, Vozzi F, D’ Acunto M, Salvadori C, Dini F, Barsotti G, Carlucci F, Burchielli S, Nicolino S, Audisio C, Perroteau I, Giusti P, Ciardelli G. Poly(ester urethane) guides for peripheral nerve regeneration. Macromol Biosci 2011; 11(2): 245–256.

    Article  CAS  Google Scholar 

  8. 8.

    Kumar AH, Martin K, Turner EC, Buneker CK, Dorgham K, Deterre P, Caplice NM. Role of CX3CR1 receptor in monocyte/ macrophage driven neovascularization. PLoS One 2013; 8(2): e57230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Clover AJ, Kumar AH, Caplice NM. Deficiency of CX3CR1 delays burn wound healing and is associated with reduced myeloid cell recruitment and decreased sub-dermal angiogenesis. Burns 2011; 37(8): 1386–1393.

    Article  Google Scholar 

  10. 10.

    Shen Z, Chen J, Kang C, Gong C, Zhu Y. Engineered hypopharynx from coculture of epithelial cells and fibroblasts using poly(ester urethane) as substratum. Biomed Res Int 2013; 2013: 138504.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Hong Y, Guan J, Fujimoto KL, Hashizume R, Pelinescu AL, Wagner WR. Tailoring the degradation kinetics of poly(ester carbonate urethane)urea thermoplastic elastomers for tissue engineering scaffolds. Biomaterials 2010; 31(15): 4249–4258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Boissard CI, Bourban PE, Tami AE, Alini M, Eglin D. Nanohydroxyapatite/poly(ester urethane) scaffold for bone tissue engineering. Acta Biomater 2009; 5(9): 3316–3327.

    Article  CAS  Google Scholar 

  13. 13.

    Field JR, Gunatillake P, Adhikari R, Ramshaw JA, Werkmeister JA. Use of biodegradable urethane-based adhesives to appose meniscal defect edges in an ovine model: a preliminary study. Aust Vet J 2008; 86(6): 229–234.

    Article  CAS  Google Scholar 

  14. 14.

    Furtado KS, Andrade FO, Comparison of the beneficial and adverse effects of inhaled and injectable anaesthetics: A minireview., OA Anaesthetics, 1 (2013) 20.

    Article  CAS  Google Scholar 

  15. 15.

    Zou X, Liu F, Zhang X, Patterson TA, Callicott R, Liu S, Hanig JP, Paule MG, Slikker W Jr, Wang C. Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. Neurotoxicol Teratol 2011; 33(5): 592–597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Agostoni M, Fanti L, Gemma M, Pasculli N, Beretta L, Testoni PA. Adverse events during monitored anesthesia care for GI endoscopy: an 8-year experience. Gastrointest Endosc 2011; 74(2): 266–275.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Sneyd JR, Holmes KA. Inhalational or total intravenous anaesthesia: is total intravenous anaesthesia useful and are there economic benefits? Curr Opin Anaesthesiol 2011; 24(2): 182–187.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ritschl LM, Fichter AM, Haberle S, von Bomhard A, Mitchell DA, Wolff KD, Mucke T. Ketamine-Xylazine Anesthesia in Rats: Intraperitoneal versus Intravenous Administration Using a Microsurgical Femoral Vein Access. J Reconstr Microsurg 2015; 31(5): 343–347.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Giroux MC, Helie P, Burns P, Vachon P. Anesthetic and pathological changes following high doses of ketamine and xylazine in Sprague Dawley rats. Exp Anim 2015; 64(3): 253–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Albrecht M, Henke J, Tacke S, Markert M, Guth B. Effects of isoflurane, ketamine-xylazine and a combination of medetomidine, midazolam and fentanyl on physiological variables continuously measured by telemetry in Wistar rats. BMC Vet Res 2015; 10: 198.

    Article  CAS  Google Scholar 

  21. 21.

    Dittmar MS, Fehm NP, Vatankhah B, Horn M. Ketamine/xylazine anesthesia for radiologic imaging of neurologically impaired rats: dose response, respiratory depression, and management of complications. Comp Med 2004; 54(6): 652–655.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wanger T, Takagaki K, Lippert MT, Goldschmidt J, Ohl FW. Wave propagation of cortical population activity under urethane anesthesia is state dependent. BMC Neurosci 2013; 14: 78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Wang K, Zhu H, Chen CY, Li P, Jin CH, Wang ZL, Jiang S, Hua TM. [Effects of ketamine and urethane on stimulation-induced cfos expression in neurons of cat visual cortex]. Dongwuxue Yanjiu 2013; 34(6): 582–588.

    CAS  PubMed  Google Scholar 

  24. 24.

    Aizawa N, Ogawa S, Sugiyama R, Homma Y, Igawa Y. Influence of urethane-anesthesia on the effect of resiniferatoxin treatment on bladder function in rats with spinal cord injury. Neurourol Urodyn 2015; 34(3): 274–279.

    Article  CAS  Google Scholar 

  25. 25.

    Liu X, Li R, Yang Z, Hudetz AG, Li SJ. Differential effect of isoflurane, medetomidine, and urethane on BOLD responses to acute levo-tetrahydropalmatine in the rat. Magn Reson Med 2012; 68(2): 552–559.

    Article  CAS  Google Scholar 

  26. 26.

    Smith PP, Kuchel GA. Continuous uroflow cystometry in the urethane-anesthetized mouse. Neurourol Urodyn 2010; 29(7): 1344–1349.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sharma AV, Wolansky T, Dickson CT. A comparison of sleeplike slow oscillations in the hippocampus under ketamine and urethane anesthesia. J Neurophysiol 2010; 104(2): 932–939.

    Article  CAS  Google Scholar 

  28. 28.

    Bertera FM, Di Verniero CA, Mayer MA, Bramuglia GF, Taira CA, Höcht C. Is urethane-chloralose anaesthesia appropriate for pharmacokinetic-pharmacodynamic assessment? Studies with carvedilol. J Pharmacol Toxicol Methods 2009; 59(1): 13–20.

    Article  CAS  Google Scholar 

  29. 29.

    Princi T, Delbello G, Grill V. Experimental urethane anaesthesia prevents digoxin intoxication: electrocardiographic and histological study in rabbit. Pharmacol Res 2000; 42(4): 355–359.

    Article  CAS  Google Scholar 

  30. 30.

    el-Mas MM, Abdel-Rahman AA. Contrasting effects of urethane, ketamine, and thiopental anesthesia on ethanol-clonidine hemodynamic interaction. Alcohol Clin Exp Res 1997; 21(1): 19–27.

    Article  Google Scholar 

  31. 31.

    Gonsenhauser I, Wilson CG, Han F, Strohl KP, Dick TE. Strain differences in murine ventilatory behavior persist after urethane anesthesia. J Appl Physiol 1985; 97(3): 888–894.

    Article  Google Scholar 

  32. 32.

    El Desoky ES, Abdulla MM. Studying long-term effect of phenytoin either alone or combined with ascorbic acid on the anesthetic effect of urethane in rats. Fundam Clin Pharmacol 2004; 18(2): 153–156.

    Article  CAS  Google Scholar 

  33. 33.

    Zorniak M, Mitrega K, Bialka S, Porc M, Krzeminski TF. Comparison of thiopental, urethane, and pentobarbital in the study of experimental cardiology in rats in vivo. J Cardiovasc Pharmacol 2010; 56(1): 38–44.

    Article  CAS  Google Scholar 

  34. 34.

    Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT. Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia. PLoS One 2008; 3(4): e2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Devonshire IM, Grandy TH, Dommett EJ, Greenfield SA. Effects of urethane anaesthesia on sensory processing in the rat barrel cortex revealed by combined optical imaging and electrophysiology. Eur J Neurosci 2010; 32(5): 786–797.

    Article  Google Scholar 

  36. 36.

    Bauquier SH, Golder FJ. The effects of urethane on the isoflurane minimum alveolar concentration in rats. Lab Anim 2010; 44(4): 323–328.

    Article  CAS  Google Scholar 

  37. 37.

    Blatt LK, Lashinger ES, Laping NJ, Su X. Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats. Neurourol Urodyn 2009; 28(5): 442–446.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Albrecht D, Blühdorn R, Siegmund H, Berger H, Calo’ G. Inhibitory action of nociceptin/orphanin FQ on functionally different thalamic neurons in urethane-anaesthetized rats. Br J Pharmacol 2001; 134 (2): 333–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Soehring K, Frahm M. [Pharmacology of alkylpolyethylene oxide derivatives. VII. Effect on circulation and respiration in cats under urethane and evipan sodium narcosis in comparison with other local analgesics]. Arzneimittelforschung 1955; 5(11): 655–662.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Duenas-García IE, Santos-Cruz LF, Castaneda-Partida L, Castaneda-Sortibran AN, Ordaz-Tellez MG, Sanchez-Santos A, Duran-Díaz A, Rodríguez-Arnaiz R, Heres-Pulido ME. Interactions of sulforaphane and dimethyl sulfoxide with methyl methanesulfonate, urethane, 4-nitroquinoline-1-oxide and hydrogen peroxide in the Drosophila melanogaster wing spot test. Food Chem Toxicol 2012; 50(12): 4479–4486.

    Article  CAS  Google Scholar 

  41. 41.

    Beland FA, Benson RW, Mellick PW, Kovatch RM, Roberts DW, Fang JL, Doerge DR. Effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice. Food Chem Toxicol 2005; 43(1): 1–19.

    Article  CAS  Google Scholar 

  42. 42.

    Sakano K, Oikawa S, Hiraku Y, Kawanishi S. Metabolism of carcinogenic urethane to nitric oxide is involved in oxidative DNA damage. Free Radic Biol Med 2002; 33(5): 703–714.

    Article  CAS  Google Scholar 

  43. 43.

    Chan PC. NTP technical report on toxicity studies of urethane in drinking water and urethane in 5% ethanol administered to F344/ N rats and B6C3F1 mice. Toxic Rep Ser 1996; 52: 1–91.

    Google Scholar 

  44. 44.

    Vorobtsova IE, Kitaev EM. Urethane-induced lung adenomas in the first-generation progeny of irradiated male mice. Carcinogenesis 1931–1934.

  45. 45.

    Ward JM, Rehm S, Devor D, Hennings H, Wenk ML. Differential carcinogenic effects of intraperitoneal initiation with 7,12-dimethylbenz(a)anthracene or urethane and topical promotion with 12-O-tetradecanoylphorbol-13-acetate in skin and internal tissues of female SENCAR and BALB/c mice. Environ Health Perspect 1986; 68: 61–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Arun H. S. Kumar.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumar, A.H.S., Clover, A.J.P. Intraperitoneal co-administration of low dose urethane with xylazine and ketamine for extended duration of surgical anesthesia in rats. Lab Anim Res 31, 174–179 (2015).

Download citation


  • Urethane
  • Xylazine
  • Ketamine
  • extended duration of surgery