Antagonistic Effects of Alpha-adrenoceptor Blocking Agents on Reticuloruminal Hypomotility Induced by Xylazine in Cattle Y. Hikasa, K. Takase, S. Emi and S. Ogasawara* ABSTRACT ber les recepteurs adrenergiques a2, a Xylazine has been characterized as savoir: 0,5 mg/kg de tolazoline et 0,2 an agonist for a2-adrenoceptors (4-11). The intravenous injection of a mg/kg de yohimbine, annula linertie In fact, various actions of xylazine, e.g. standard dose (0.05 mg/kg) of xyla- du reseau et du rumen provoquee par sedation in mice and chickens (8), zine inhibited reticuloruminal motility la xylazine. La tolazoline s'avera plus analgesia in rats and mice (12), in cattle. Pretreatment with adreno- efficace que la yohimbine, puisque 0,5 inhibition of small intestinal motility in ceptor antagonists showing a2- mg/kg de yohimbine ne provoqua pas mice (13), hyperglycemia associated blocking activity, tolazoline (0.5 mg/ d'effet antagoniste et que 0,2 mg/kg de with inhibition of insulin release in kg) and yohimbine (0.2 mg/kg), yohimbine se revela moins efficace que cattle (14) and emesis in dogs (7), were antagonized the xylazine-induced 0,5 mg/kg de tolazoline. La prazosine, reported to be antagonized by agents reticuloruminal amotility. Tolazoline un antagoniste des recepteurs adrener- possessing a2-adrenoceptor blocking was more effective than yohimbine, giques al n'empecha pas linhibition de activity such as yohimbine, tolazoline, since an antagonistic effect was not la mobilite du reseau et du rumen due a piperoxan and phentolamine (15-18). seen at 0.5 mg/kg yohimbine, and la xylazine. Linjection de domperi- In these studies, yohimbine was found yohimbine at 0.2 mg/kg was less done, un antagoniste des recepteurs de to be the most effective agent for effective than tolazoline at 0.5 mg/kg. la dopamine, et celle de naloxone, un antagonism of the actions of xylazine. An adrenoceptor antagonist showing antagoniste des recepteurs d'opiate, ne In cattle, however, yohimbine is a,-blocking activity, prazosin, did not reussirent pas non plus a empecher ineffective in antagonizing xylazine- prevent the inhibition of reticulorumi- l'inhibition de la motilite du reseau et induced sedation (1), although tolazo- nal motility by xylazine. The xylazine- du rumen due a la xylazine. Les line antagonizes xylazine-induced induced reticuloruminal amotility was resultats de cette experience sous- central nervous system (CNS) depres- also not prevented by either a entendent que la xylazine inhibe la sion (2,19). As yohimbine is the most dopamine receptor antagonist, motilite du reseau et du rumen, chez les effective agent for blocking a2- domperidone, or an opiate receptor bovins, en activant les recepteurs adrenoceptors (16,18), its inability to antagonist, naloxone. These results adrenergiques a2; ils demontrent aussi antagonize the xylazine-induced seda- suggest that xylazine inhibits bovine la possibilite d'utiliser la tolazoline tion focuses attention on the receptive reticuloruminal motility through its comme antagoniste specifique de la mechanism of xylazine actions in the activation of a2-adrenoceptors, and xylazine, au cours d'etudes relatives a bovine CNS. It has been shown that show that tolazoline can be used as a l'influence des recepteurs adrener- xylazine-induced inhibition of reticu- specifilc antagonist of xylazine in giques sur la motilite du reseau et du lar motility in sheep is an effect studies of the a-adrenergic influence rumen, chez les bovins. resulting from the central activity of on reticuloruminal motility in cattle. xylazine (10,20), and so it seems of interest to examine whether the INTRODUCTION xylazine-induced reticuloruminal RESUME amotility in cattle is mediated by a2- Xylazine hydrochloride is widely adrenoceptors. L'injection intraveineuse d'une dose used in veterinary medicine as a Several attempts have been made to standard de 0,05 mg/kg de xylazine sedative, analgesic and muscle relaxant reverse the reticuloruminal amotility in inhiba la motilite du reseau et du agent. In particular, cattle are highly cattle induced by xylazine (1-3). As a rumen, chez des bovins. L'injection sensitive to xylazine. It is also known result, the xylazine-induced ruminal prealable d'antagonistes des recep- that this agent inhibits reticuloruminal amotility was reported to be reversed teurs adrenergiques, capables d'inhi- motility in cattle (1-3). by tolazoline (2,3) and yohimbine (1). *Department of Veterinary Surgery, School of Veterinary Medicine and Animal Sciences, Kitasato University, Towada-shi, Aomori 034, Japan. Submitted November 20, 1987. Can J Vet Res 1988; 52: 411-415 41 The xylazine-induced reticular amotil- TABLE I. Effects of a-Adrenoceptor, Dopamine and Opiate Receptor Blocking Agents on the ity was reported to be reversed by tola- Xylazine-induced Inhibition of Ruminal Motility in Cattle zoline (3). More recently, Ruckebusch Dose Number Duration of Ruminal Amotility and Allal (21) reported that the inhibi- Pretreatmenta (mg/kg) of Cows (Mean ± SD, Minutes) tion of bovine reticuloruminal contrac- None (Control) 5 48.0 ± 12.5 tions induced by xylazine was reversed Tolazoline 0.5 6 17.5 ± 10.4b by yohimbine and tolazoline. However, Yohimbine 0.2 5 29.0 ± 2.2c the receptor mechanism of the xyla- 0.5 6 37.5 12.5 reticuloruminal amotility Prazosin 0.5 5 54.0 ± 17.1 zine-induced Domperidone 0.5 5 69.0 ± 22.7 in cattle has not been well elucidated. Naloxone 0.1 5 51.0 ± 13.4 The present study was conducted to aPotential antagonists were injected intravenously ten minutes before the intravenous injection of determine whether xylazine-induced xylazine (0.05 mg/kg) inhibition ofreticuloruminal motility in bp < 0.01, cp < 0.05, when compared to the control group, that received xylazine only cattle is mediated by a2-adrenoceptors and whether this effect involves other receptor types. scopy. X-ray exposure was performed tolazoline hydrochloride (Imidalin®, continuously for 3 min with a horizon- 2% solution; Yamanouchi Pharma- MATERIALS AND METHODS tal X-ray beam, at 200 kVP and 4 mAs, ceutical Co. Ltd., Japan); and domperi- with an anode distance of 80 cm. The done (Nauzelin®, 0.2% solution; ANIMALS frequency of biphasic contractions of Kyowa Hakko Ind. Co. Ltd., Japan). Eleven nonlactating cows, ten the reticulum per 3 min was recorded Xylazine, tolazoline and domperidone Holsteins and one Jersey (4 to 11 years prior to drug administration, and then were used as the undiluted 2%, 2% and of age), weighing from 408 to 611 kg at 5, 15, 30, 45, 60, 75, 90, 105 and 120 0.2% solutions, respectively. Yohim- (mean 545 kg ± 63 SD), were used in min after the xylazine injection. The bine, naloxone and prazosin were this study. They were housed indoors at duration of reticular amotility (fre- dissolved in distilled water. All dosages night and kept outdoors during the day, quency of biphasic contractions, 0 per 3 were calculated on the basis of the drug and given a commercial cattle concen- min) was determined. base weight. trate, hay and water ad libitum. The Ruminal motility was measured by a animals were randomly used for each stethoscopic method. A stethoscope STATISTICAL ANALYSIS experiment. The same animal was not was attached to the left side of the The data were subjected to analysis used repeatedly more than five times. abdomen. The ruminal sounds were of variance and Student's t-test The experiments were performed in a monitored in the intervals between the (p < 0.05) (22). large animal X-ray room with the X-ray exposures. After the xylazine temperature controlled at 20 ± 10 C. injection, the duration of ruminal Food and water were withheld during amotility (no ruminal sounds per 3 min) RESULTS the was determined. experiments. EFFECTS OF a2-ADRENOCEPTOR, EXPERIMENTAL GROUPS MEASUREMENT OF SEDATION DOPAMINE AND OPIATE RECEPTOR The animals were used in seven Additionally, the duration of seda- BLOCKING AGENTS ON THE XYLAZINE- groups of five to six cows each. The tion was measured in this study. The INDUCED INHIBITION OF RUMINAL groups comprised nonpretreated con- intravenous injection of xylazine MOTILITY trols and cows pretreated with yohim- (0.05 mg/ kg) induced CNS depression, The results are summarized in Table bine at 0.2 mg/kg bodyweight which was characterized by transient I. The ruminal sound frequency was (0.04 mL/ kg) and 0.5 mg/kg body- recumbency, knuckling of the fetlock approximately 1 per min prior to drug weight (0.07 mL/kg), tolazoline at joints, head-down posture, open-limbs administration. In the control cows, 5 0.5 mg/kg (0.025 mL/kg), prazosin at and unsteady walking. The duration of min after the intravenous injection of 0.5 mg/ kg (0.05 mL/ kg), domperidone xylazine-induced sedation was taken as xylazine (0.05 mg/kg bodyweight) at 0.5 mg/kg (0.25 mL/kg) and nalox- the time between initial knuckling of ruminal sounds had disappeared. The one at 0.1 mg/ kg (0.01 mL/ kg). Cows the fetlock joints and head-down mean duration of ruminal amotility in each group received a single intraven- posture and the time of recovery from was 48 min. Pretreatment with an a2- ous injection of xylazine at the dosage all effects described above. blocker, tolazoline (0.5 mg/ kg), greatly of 0.05 mg/kg bodyweight (0.0025 reduced the duration of ruminal mL/ kg). All the potential antagonists DRUGS USED amotility induced by xylazine. A were injected intravenously 10 min The drugs used and their sources second a2-blocker, yohimbine, at before the xylazine administration. were as follows: xylazine hydrochloride 0.5 mg/kg did not significantly reduce (Celactal®, 2% solution; Bayer Japan); the duration of xylazine-induced MEASUREMENTS OF RUMINAL yohimbine hydrochloride and nalox- rumen amotility.