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. 2022 Mar;38(2):156-166.
doi: 10.1089/jop.2021.0084. Epub 2021 Dec 29.

Comparisons of α2-Adrenergic Agents, Medetomidine and Xylazine, with Pentobarbital for Anesthesia: Important Pitfalls in Diabetic and Nondiabetic Rats

Anna R Connell  1 , Michelle B Hookham  1 , Dongxu Fu  1   2   3 , Derek P Brazil  1 , Timothy J Lyons  1   2   3 , Jeremy Y Yu  1   2
Affiliations

Comparisons of α2-Adrenergic Agents, Medetomidine and Xylazine, with Pentobarbital for Anesthesia: Important Pitfalls in Diabetic and Nondiabetic Rats

Anna R Connell et al. J Ocul Pharmacol Ther. 2022 Mar.

Abstract

Purpose: Anesthesia is necessary to conduct rodent electroretinograms (ERGs). We evaluated utility of the α2-agonist medetomidine versus xylazine for ERG studies in nondiabetic and diabetic rats. Pentobarbital was included as a comparator. Methods: Male Sprague-Dawley rats, with and without streptozotocin (STZ)-induced diabetes, were anesthetized with medetomidine (1 mg/kg), xylazine (10 mg/kg) (both with ketamine 75 mg/kg), or pentobarbital (70 mg/kg). The depth of anesthesia was assessed, and if adequate, scotopic ERGs were recorded. Blood glucose was monitored. Results: In nondiabetic rats, all three agents induced satisfactory anesthesia, but with differing durations: medetomidine > pentobarbital > xylazine. ERG responses were similar under medetomidine and xylazine, but relatively reduced under pentobarbital. Both α2-agonists (but not pentobarbital) elicited marked hyperglycemia (peak values 316.1 ± 42.6 and 300.3 ± 29.5 mg/dL, respectively), persisting for 12 h. In diabetic rats, elevated blood glucose concentrations were not affected by any of the agents, but the depth of anesthesia under medetomidine and xylazine was inadequate for ERG recording. Conclusions: In nondiabetic rats, medetomidine and xylazine elicited comparable effects on ERGs that differ from pentobarbital, but both perturbed glucose metabolism, potentially confounding experimental outcomes. In STZ-diabetic rats, neither α2-agent provided adequate anesthesia, while pentobarbital did so. Problems with α2-anesthetic agents, including medetomidine, must be recognized to ensure meaningful interpretation of experimental results.

Keywords: anesthesia; diabetes; electroretinogram; hyperglycemia; medetomidine; α2 adrenoceptor.

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Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Time course anesthetic effects of α2-adrenoceptor agonists and pentobarbital in nondiabetic and STZ-induced diabetic rats. Animals were administered with medetomidine 1 mg/kg (n = 6), xylazine 10 mg/kg (n = 6; both combined with ketamine 75 mg/kg), or pentobarbital 70 mg/kg (n = 5). Anesthetic depth was assessed by pedal (upper), tail (middle), and corneal reflexes (lower) over 2 h. Data were expressed as % animals showing a positive neural reflex at each time point. Diamond: medetomidine/ketamine; square: xylazine/ketamine; triangle, perforated line: pentobarbital. #Medetomidine/ketamine versus pentobarbital; *xylazine/ketamine versus pentobarbital; xmedetomidine/ketamine versus xylazine/ketamine. #/*/xP ≤ 0.05, ##/**/xxP ≤ 0.01, ###/***/xxxP ≤ 0.001. STZ, streptozotocin.
FIG. 2.
FIG. 2.
Representative full-field scotopic ERG recordings from nondiabetic rats. Animals were dark adapted overnight, and then anesthetized with medetomidine (1 mg/kg), xylazine (10 mg/kg; both combined with ketamine 75 mg/kg), or pentobarbital (70 mg/kg). The pupil was dilated with topical 2.5% (w/v) phenylephrine and 1% (w/v) atropine. ERGs were recorded by a color miniature Ganzfeld, using gold electrodes placed on the cornea and the reference and ground electrodes at the nasal fornix and tail, respectively. Waveforms between light intensities of 0.008–25 cd*s/m2 are shown. Scale bar indicates 50 μV and 10 ms. ERG, electroretinogram.
FIG. 3.
FIG. 3.
A- and b-wave ERG responses from nondiabetic rats. ERGs were recorded as in Figure 2. Data (a-waves in panels A and C; b-waves in panels B and D) are summarized as light intensity–response curves for the amplitude, and as average responses across the light intensity range for the implicit time. Mean ± SD, n = 4–5 per anesthetic regimen. Diamond: medetomidine/ketamine; square: xylazine/ketamine; triangle, perforated line: pentobarbital. #Medetomidine/ketamine versus pentobarbital; *xylazine/ketamine versus pentobarbital; xmedetomidine/ketamine versus xylazine/ketamine. #/*/xP ≤ 0.05, ##/**/xxP ≤ 0.01, ###/***/xxxP ≤ 0.001, ####/****/xxxxP ≤ 0.0001. SD, standard deviation.
FIG. 4.
FIG. 4.
Filtered scotopic OPs from nondiabetic rats. (A) Representative OPs under anesthesia with (a) medetomidine/ketamine, (b) xylazine/ketamine, and (c) pentobarbital. ERGs were recorded in response to the light intensity of 25 cd*s/m2, with a 75 Hz low-pass filter. Calculations for the amplitude are illustrated. (B) Amplitudes and implicit times of individual OPs and sum of OP1-5 (ΣOP), expressed as mean ± SD, n = 3 per anesthetic regimen. #Medetomidine/ketamine versus pentobarbital; *xylazine/ketamine versus pentobarbital; xmedetomidine/ketamine versus xylazine/ketamine. #/*/xP ≤ 0.05, ##/**/xxP ≤ 0.01, ###/***/xxxP ≤ 0.001. OPs, oscillatory potentials.
FIG. 5.
FIG. 5.
Blood glucose concentration changes by α2-adrenoceptor agonists and pentobarbital in nondiabetic rats. Animals received medetomidine 1 mg/kg (n = 6), xylazine 10 mg/kg (n = 6; both combined with ketamine 75 mg/kg), or pentobarbital 70 mg/kg (n = 5), versus without anesthesia (n = 6). Blood glucose concentrations were measured for 24 h after administration and expressed as mean ± SD. #Medetomidine/ketamine versus nonanesthetized; *xylazine/ketamine versus anesthetized. #/*P ≤ 0.05, ##/**P ≤ 0.01, ###/***P ≤ 0.001.
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