Antagonistic Effects of Alpha-adrenoceptor Blocking Agents on Reticuloruminal Hypomotility Induced by 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 for a2-adrenoceptors (4-11). The intravenous injection of a mg/kg de , 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 and (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 , 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, , 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 , 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- 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. But, yohimbine at a AND RETICULAR MOTILITY one hydrochloride (Sigma, St. Louis, lower dose (0.2 mg/kg) significantly Reticular motility was examined by Missouri); prazosin hydrochloride reduced the xylazine-induced inhibi- means of right-lateral X-ray fluoro- (Tokyo Kasei, Ind. Co. Ltd., Japan); tion of ruminal motility. The duration

412 TABLE II. Effects of a-Adrenoceptor, Dopamine and Opiate Receptor Blocking Agents on the tolazoline at 0.6 mg/kg well antagon- Xylazine-induced Inhibition of Reticular Motility in Cattle ized reticular amotility induced by Dose Number Duration of Reticular Amotility xylazine at 0.4 mg/kg intravenously. Pretreatmenta (mg/kg) of Cows (Mean ± SD, Minutes) Also, yohimbine at 0.25 mg/ kg intrav- None (Control) 5 51.0 ± 17.1 enously has been reported to reduce the Tolazoline 0.5 6 15.0 ± 8.4b duration of bovine ruminal amotility Yohimbine 0.2 5 32.0 ± 4.5C induced by xylazine at 0.05 mg/kg 0.5 6 46.2± 12.1 intravenously (1). Furthermore, tolazo- Prazosin 0.5 5 57.0 ± 12.5 Domperidone 0.5 5 54.0 ± 13.4 line at 0.2-1.0 mg/ kg intravenously has Naloxone 0.1 5 54.0 ± 22.7 been reported to reverse the inhibition aPotential antagonists were injected intravenously ten minutes before the intravenous injection of of bovine reticuloruminal motility xylazine (0.05 mg/ kg) induced by xylazine at 0.1 mg/kg bp < 0.oo, Cp < 0.05, when compared to the control group, that received xylazine only intramuscularly (3). Based on these ob- servations, the dosages ofa-antagonists were determined in this study. The of xylazine-induced ruminal amotility prevented the xylazine-induced recum- results of the present study suggest that was not reduced by an a1-adrenoceptor bency and reduced the duration of the xylazine-induced inhibition of antagonist, prazosin (0.5 mg/kg), a xylazine-induced sedation. In contrast, bovine reticuloruminal motility is dopamine receptor antagonist, yohimbine at the doses (0.2 and mediated by a2-adrenoceptors, as (a) an domperidone (0.5 mg/kg), or an opiate 0.5 mg/kg) used did not affect the adrenoceptor antagonist showing a2- receptor antagonist, naloxone (0.1 mg/ duration of xylazine-induced sedation. blocking activity, yohimbine (16-18) at kg). Also, the depressant effect of xylazine the low dose (0.2 mg/ kg) studied, was not antagonized by prazosin reduced the xylazine-induced reticulo- EFFECTS OF a-ADRENOCEPTOR, (0.5 mg/ kg), domperidone (0.5 mg/ kg) ruminal amotility; (b) another a2- DOPAMINE AND OPIATE RECEPTOR or naloxone (0.1 mg/kg). blocker, tolazoline (6,17,18) at 0.5 mg/ BLOCKING AGENTS ON THE XYLAZINE- kg, greatly reduced the reticuloruminal INDUCED INHIBITION OF RETICULAR amotility induced by xylazine; and (c) MOTILITY DISCUSSION an adrenoceptor antagonist showing The results are summarized in Table a,-blocking activity, prazosin (16-18) at II. Biphasic contractions of the The results ofthe present study show 0.5 mg/kg, did not reduce the xylazine- reticulum occurred at a frequency of that a standard dose of xylazine (0.05 induced inhibition of reticuloruminal approximately three per 3 min prior to mg/kg bodyweight) inhibits reticulo- motility. The results further support the drug administration. In the control ruminal motility in cattle. These hypothesis that activation of aL2- cows, 5 min after the intravenous findings are in agreement with those adrenoceptors inhibits the cyclical injection of xylazine (0.05 mg/kg previously reported (1-3). In sheep, it motor activity of the bovine reticuloru- bodyweight) the frequency had has been shown that xylazine inhibits men, which was recently reported by decreased to zero per 3 min. The mean reticular contractions through the Ruckebusch and Allal (21). duration of reticular amotility was activation ofa2-adrenoceptors, because The present findings also show that 51 min. Pretreatment with tolazoline this effect is competitively antagonized the xylazine-induced reticuloruminal (0.5 mg/kg) greatly reduced the dura- by a2-adrenoceptor antagonists, but amotility is not mediated by dopamine tion of reticular amotility. Yohimbine not by a1-adrenoceptor antagonists or opiate receptors, since a dopamine at 0.5 mg/kg did not significantly (10). In that report, intravenous receptor antagonist, domperidone reduce the xylazine-induced reticular yohimbine at 0.2-0.3 mg/kg and (23) (0.5 mg/ kg), and an opiate receptor amotility. But, yohimbine at the lower dose (0.2 mg/kg) signiflcantly reduced the duration of xylazine-induced reticular amotility. Prazosin (0.5 mg/ TABLE III. Effects of a-Adrenoceptor, Dopamine and Opiate Receptor Blocking Agents on the kg), domperidone (0.5 mg/kg) and Xylazine-induced Sedation in Cattle naloxone (0.1 mg/ kg) did not affect the Dose Number Duration of Sedationb xylazine-induced reticular amotility at Pretreatmenta (mg/kg) of Cows (Mean ± SD, Minutes) all. None (Control) 5 93.0 ± 16.4 Table III shows the effects of Tolazoline 0.5 6 45.0 ± 19.0c tolazoline, yohimbine, prazosin, Yohimbine 0.2 5 91.6 ± 31.7 0.5 6 105.3 28.5 domperidone and naloxone on Prazosin 0.5 5 105.0 ± 38.2 xylazine-induced sedation. Xylazine Domperidone 0.5 5 102.0 ± 16.4 alone caused CNS depression, which Naloxone 0.1 5 108.0 ± 22.2 was characterized by transient recum- bency, knuckling of the fetlock joints, 'Potential antagonists were injected intravenously ten minutes before the intravenous injection of xylazine (0.05 mg/ kg) head-down posture, open-limbs and bTime when transient recumbency, knuckling ofthe fetlockjoints, head-down posture, open-limbs and unsteady walking. Pretreatment with unsteady walking all disappeared after the xylazine injection tolazoline (0.5 mg/kg) completely Cp < 0.01, when compared to the control group, that received xylazine only

413 antagonist, naloxone (0.1 mg/kg), mice (13) and dogs (29) and emesis in findings are in agreement with those failed to reduce the effect of xylazine. dogs (7), have been shown to be more previously reported (1,2,19). The However, it has been shown that at the effectively antagonized by yohimbine ineffectiveness of yohimbine in block- doses used in this study, domperidone than tolazoline. In the present study, ing the xylazine-induced sedation, in completely prevents the inhibition of however, xylazine-induced hypomotil- part, could explain the fact that the ruminal motility induced by intraven- ity of the rumen and reticulum was not antagonism of xylazine-induced hypo- ous (0.3 mg/kg) or antagonized by yohimbine at 0.5 mg/ motility by yohimbine is lower than dopamine (0.02 mg/kg) in goats (24), kg bodyweight, while tolazoline at the that by tolazoline, since reticulorumi- and naloxone not only antagonizes the same dose did antagonize the xylazine- nal motility is inhibited by a reduction morphine-induced ruminal amotility induced hypomotility. Furthermore, in the net excitatory drive to the gastric but even stimulates ruminal motility in yohimbine at 0.2 mg/kg reduced the centre through depression ofthe central goats (25). hypomotility induced by xylazine, but neuronal circuit (27). On the other Extrinsic contraction of the rumen the reduction was less than that with hand, yohimbine may affect serotoner- and reticulum in ruminants is under tolazoline at 0.5 mg/kg. These findings gic, cholinergic, dopaminergic and the control of the gastric centre, show that tolazoline is more effective GABA receptor-related mechanisms, located in an area of the dorsal vagal than yohimbine as an antagonist of and may exhibit various actions such as nucleus of the medulla oblongata, xylazine-induced reticuloruminal a local anesthetic effect, acetylcholines- through the afferent and efferent hypomotility in cattle. Also, the terase inhibition or monoamine oxi- pathways of the vagal nerves (26,27). antagonism of xylazine-induced hypo- dase inhibition (30), suggesting that The exact site of action of xylazine on motility by tolazoline seems to be potential actions of yohimbine other the reticuloruminal motility is uncer- clinically important. than the blockading of a2-adrenocep- tain. In sheep, the intracerebroventric- Although yohimbine is the most tors may interfere with the reversal of ular administration of xylazine was effective drug for blocking a2- the reticuloruminal hypomotility shown to inhibit reticular contractions adrenoceptors (16-18), the reason for induced by xylazine in cattle. Also, it (20). In addition, in sheep given the ineffectiveness of yohimbine at the was recently reported that subtypes of xylazine, electrical stimulation of the high dose in antagonizing the xylazine- a2-adrenoceptors having different peripheral end of the vagus was induced reticuloruminal amotility is neuronal locations, functions and reported to elicit reticular contrac- unknown. However, Ruckebusch and pharmacological properties may exist tions (10). These findings show that Allal (21) recently reported that, in the rat brain (31), and so it is possible xylazine inhibits reticular contrac- although tolazoline and yohimbine that the differences between yohimbine tions by acting at the CNS without both reversed the inhibition of reticulo- and tolazoline in antagonism of the impairing cholinergic transmission at ruminal contractions induced by xylazine-induced hypomotility in cattle the peripheral levels. Toutain et al (I0) xylazine in sheep and cattle, only may be due to the existence of such obtained evidence that central a2- tolazoline was able to antagonize the subtypes of a2-adrenoceptors. adrenoceptors mediate the inhibition inhibition of secondary ruminal con- In conclusion, the results of this of reticular contraction by xylazine in tractions in sheep and alleviate accumu- study suggest that xylazine-induced sheep. In addition, the a2-adreno- lation of gas in the rumen in cattle, reticuloruminal amotility in cattle is ceptors have been shown to be located while yohimbine did not show these mediated by a2-adrenoceptors. This ef- in the CNS, and to be abundant in the effects and higher doses of yohimbine fect does not appear to involve al- dorsal vagal nucleus of the medulla further impaired the amount of gas adrenergic, dopamingeric or opiate oblongat (28). Furthermore, a- eructated. Furthermore, yohimbine at pathways. The present results also adrenoceptors controlling reticulo- the doses higher than 0.4 mg/ kg per se indicate that tolazoline can be used as a ruminal motility are located in the was shown to inhibit the frequency of specific antagonist of xylazine in CNS (27). These observations and our ruminal contractions with an increase studies on the a-adrenergic influence on results strongly suggest that the in the lower oesophageal sphincter reticuloruminal motility in cattle, and it xylazine-induced inhibition of bovine pressure and an increase in the intrinsic can be used clinically for the treatment reticuloruminal motility is mediated smooth muscle tone of the reticulum in of xylazine-induced hypomotility and by central a2-adrenoceptors. How- cattle (21). Thus, the ineffectiveness of bloating in cattle. ever, as a-receptors also exist in yohimbine at the high dose (0.5 mg/kg) smooth muscle of the rumen and in antagonizing xylazine-induced reticulum (27), the possibility could reticuloruminal hypomotility observed ACKNOWLEDGMENTS not be eliminated that peripheral as in this study, in part, might be due to The authors wish to thank Mr. N. well as central sites are involved in the the nonalleviation of the accumulation Ide for his skilful technical assistance. depressant effect of xylazine. of gas resulting from inhibition of the In monogastric species, yohimbine secondary ruminal contractions and seems to be a better antagonist than the increase in the intrinsic smooth REFERENCES tolazoline for reversal of various muscle tone of the reticulum by actions of For yohimbine. The results of the present 1. GUARD CL, SCHWARK WS. 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