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J. Vet. Med. A, 34, 58-60 (1987) 0 1987 Paul Parey Scientific Publishers, Berlin and Hamburg ISSN 0931-184X From the Laboratory of Physiology, Veterinary Faculty, Aristotelian University, 540 06 Thessaloniki, Greece Xylazine-Induced Hyperglycaemia and a-Adrenergic Receptors in Sheep P. BRIKAS', C. TSIAMITAS, and A. AYIANNIDIS' Address of authors: Veterinary Faculty, Aristotelian University, 540 06 Thessaloniki, Greece I Laboratory of Physiology, * Clinic of Internal Medicine With one figure (Received for publication April 22, 1986) Summary Intravenous injection of the a-adrenergic receptors agonist xylazine (0.3 mg/kg b. w.) produced hyperglycaemia with its peak (110 mg/100 ml) 30 min later in sheep. This hyperglycaemia was statistically significant for 3 hours. When xylazine was administered after pretreatment of the animals with either the a,-adrenergic receptors blocker prazosin (0.5 mg/kg i. v.) or the a2-blocker yohimbine (0.5 mg/kg i. v.) a hyperglycaemia was also produced but in the case of prazosin its peak did not exceed 95 mg/100 ml, and in the case of yohimbine it was only 70 mg/100 ml (control value 55 mg/ lOOml). When animals were pretreated with either yohimbine plus prazosin or the a,- and a,-blocker tolazoline (3 mg/kg i. v.) the hyperglycaemic effect of xylazine was inhibited. These results suggest that, in the regulation of blood glucose levels by the a-adrenergic receptors, the a, play the main role, while the a, are also involved. Key words: Xylazine, hyperglycaemia, adrenergic receptors Introduction Xylazine, a widely used veterinary drug for its good sedative, analgesic and muscle relaxant properties, is known to produce a pronounced hyperglycaemia. It has been suggested that xylazine acts by increasing the rate of glucose output by the liver, elevating the concentrations of glucagon and grouth hormone and reducing those of insulin in the blood (SYMONDS, 1976; SYMONDS and MALLINSON, 1978; EICHNER etal., 1979; BROCK- MAN, 1981; HAMPSHIRE and ALTSZULER, 1981; Hsu and HUMMEL, 1981). It has been reported that this xylazine-induced hyperglycaemia is mediated predominantly by az- adrenergic receptors, but it is possible that this drug also stimulates hepatic glucose output through a weak a,-agonistic effect (Hsu and HUMMEL, 1981). The present study has been carried out to obtain further information on the involvement of the a-adrenergic receptors in the regulation of blood glucose levels in sheep. Material and Methods Eight ewes (Chios x local crosses), non-pregnant, non-lactating, 2 to 5 years old and weighing 3C-35 kg were used. They were given hay and water ad libitum. Each animal was accustomed to handling and was used for experiment only once a week. U.S. Copyright Clearance Center Codc Statement: 0931-1 84X/87/3401-0058$02.50/0

Xylazine-Induced Hyperglycaemia and α-Adrenergic Receptors in Sheep

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Page 1: Xylazine-Induced Hyperglycaemia and α-Adrenergic Receptors in Sheep

J. Vet. Med. A, 34, 58-60 (1987) 0 1987 Paul Parey Scientific Publishers, Berlin and Hamburg ISSN 0931-184X

From the Laboratory of Physiology, Veterinary Faculty, Aristotelian University, 540 06 Thessaloniki, Greece

Xylazine-Induced Hyperglycaemia and a-Adrenergic Receptors in Sheep

P. BRIKAS', C. TSIAMITAS, and A. AYIANNIDIS'

Address of authors: Veterinary Faculty, Aristotelian University, 540 06 Thessaloniki, Greece I Laboratory of Physiology, * Clinic of Internal Medicine

With one figure

(Received for publication April 22, 1986)

Summary Intravenous injection of the a-adrenergic receptors agonist xylazine (0.3 mg/kg b. w.) produced

hyperglycaemia with its peak (1 10 mg/100 ml) 30 min later in sheep. This hyperglycaemia was statistically significant for 3 hours. When xylazine was administered after pretreatment of the animals with either the a,-adrenergic receptors blocker prazosin (0.5 mg/kg i. v.) or the a2-blocker yohimbine (0.5 mg/kg i. v.) a hyperglycaemia was also produced but in the case of prazosin its peak did not exceed 95 mg/100 ml, and in the case of yohimbine it was only 70 mg/100 ml (control value 55 mg/ lOOml). When animals were pretreated with either yohimbine plus prazosin or the a,- and a,-blocker tolazoline ( 3 mg/kg i. v.) the hyperglycaemic effect of xylazine was inhibited. These results suggest that, in the regulation of blood glucose levels by the a-adrenergic receptors, the a, play the main role, while the a, are also involved.

Key words: Xylazine, hyperglycaemia, adrenergic receptors

Introduction Xylazine, a widely used veterinary drug for its good sedative, analgesic and muscle

relaxant properties, is known t o produce a pronounced hyperglycaemia. I t has been suggested that xylazine acts by increasing the rate of glucose ou tpu t by the liver, elevating the concentrations of glucagon and grouth hormone and reducing those of insulin in the blood (SYMONDS, 1976; SYMONDS and MALLINSON, 1978; EICHNER etal., 1979; BROCK- MAN, 1981; HAMPSHIRE and ALTSZULER, 1981; Hsu and HUMMEL, 1981). It has been reported that this xylazine-induced hyperglycaemia is mediated predominantly by az- adrenergic receptors, bu t it is possible that this d rug also stimulates hepatic glucose ou tpu t through a weak a,-agonistic effect (Hsu and HUMMEL, 1981). T h e present s tudy has been carried ou t to obtain further information on the involvement of the a-adrenergic receptors in the regulation of blood glucose levels in sheep.

Material and Methods Eight ewes (Chios x local crosses), non-pregnant, non-lactating, 2 to 5 years old and weighing

3C-35 kg were used. They were given hay and water ad libitum. Each animal was accustomed to handling and was used for experiment only once a week.

U.S. Copyright Clearance Center Codc Statement: 0931-1 84X/87/3401-0058$02.50/0

Page 2: Xylazine-Induced Hyperglycaemia and α-Adrenergic Receptors in Sheep

Xylazine-Induced Hyperglycaemia 59

Blood samples of 3 ml from a jugular vein through a permanently indwelling catheter were taken immediately before (zero time) and thereafter at 15 min intervals for 4 hours after the i. v. injection of the substances used.

The following series of experiments were carried out: a) Control experiments with i) 0.3 mg/kg b. w. of xylazine (Rompuna, Bayer AG), ii) 3 mg/kg

of tolazoline HCl (Sigma Chemical Co.), iii) 0.5 mg/kg of yohimbine HC1 (Sigma Chemical Co.), and iv) 0.5 mg/kg of prazosin HCI (Pfizer Hellas A. E.).

b) Experiments with xylazine (0.3 mg/kg) injected 2 rnin after the administration of i) 3 mg/kg of tolazoline, ii) 0.5 mg/kg of yohimbine, iii) 0.5 mg/kg of prazosin, and iv) 0.5 mg/kg of yohimbine plus 0.5 mg/kg of prazosin.

Each series of experiments was repeated three times on every animal. Blood glucose was estimated by means of a glucose oxidase procedure using a commercial kit

(Boehringer Mannheim GmbH). The results are expressed as means _+ SEM. Significance for the post-injection mean values was

evaluated by comparing each one which the control value, using the student's paired t test. In all cases a value of P < 0.05 was considered significant.

Results In the control experiments, xylazine produced a large increase in blood glucose

concentrations which reached its peak (1 10 mg/IOO ml) 30 min after the injection. The blood glucose concentrations remained high for about 90 min and thereafter a significant hyperglycaemia continued for another 90 rnin (Fig. 1). In contrast, tolazoline, yohimbine and prazosin did not produce any effect on blood glucose levels.

Xylazine administered after pretreatment of the animals with tolazoline or yohimbine plus prazosin failed to provoke any rise in blood glucose levels. When animals were pretreated with only yohimbine or prazosin, the effect of the administration of xylazine was as follows: in the case of pretreatment with yohimbine a slight, but significant, increase in blood glucose concentration (70 mg/100 ml versus 55 mg/100 ml of the control value), which lasted for about 150min, was seen; in the case of prazosin, xylazine administration induced for about 3 hours a pronounced hyperglycaemia, whose levels (95 mg/100 ml) did not reach those produced by xylazine alone (Fig. 1).

- F 100-

P

a 0 e \

- I

0 3

0)

Q

0

m

- ?

50 -

0

o---u x y l a z i n e o ...... o prazosin + x y l a z i n e

A-A yohimbine t x y l a z i n e

r l l l l l , l l r ~ l i t i i l

0 30 60 90 120 150 180 210 240 min

Fig. 1. Effect on sheep blood glucose concentrations of i. v. administration of xylazine alone (0.3 mg/ kg b. w., upper curve); xylazine after i. v. pretreatment of the animals with prazosin (0.5 mg/kg, middle curve) or yohimbine (0.5 mg/kg, lowest curve). The points represent mean values (n = 24 from 8 animals). Vertical bars show the SEM and open symbols indicate a significant change (p < 0.05)

Page 3: Xylazine-Induced Hyperglycaemia and α-Adrenergic Receptors in Sheep

60 BRIKAS, TSIAMITAS and AYIANNIDIS

Discussion NAKADATE etal. (1980a, 1980b), working on mice, found that epinephrine failed to

induce hyperglycaemia in animals pretreated with phentolamine, yohimbine or dihydroer- gotamine and suggested that the receptors responsible for the regulation of blood glucose levels differ from the classical a-adrenergic receptors and more closely resemble a2- adrenergic ones. HSU and HUMMEL (1981), working on cows and using phentolamine or yohimbine or prazosin as a-adrenergic receptor blocking agents, concluded that xylazine- induced hyperglycaemia is predominantly mediated by az-adrenergic receptors; they also showed that xylazine in dogs caused both a2- and al-agonistic effects on the cardiovascular system. These authors, based on a slight reduction of the xylazine-induced hyperglycaemia by the al-adrenergic receptors blocking agent prazosin, put forward the hypothesis that such receptors in the liver of cattle may also be involved in the regulation of glycaemia.

In the present work on sheep, when the animals were pretreated with either prazosin (as an al-blocker) or yohimbine (as an a2-blocker), xylazine continued to produce a hyperglycaemic effect. However, this hyperglycaemia, compared to that produced by xylazine alone in the control experiments, was slightly lower in the case of prazosin, and much lower in the case of yohimbine. O n the other hand, when the animals were pretreated with either yohimbine plus prazosin or tolazoline (as an al- and a2-blocker) the hyperglycaemic efficacy of xylazine was abolished. Since yohimbine greatly reduces the hyperglycaemic effect of xylazine, it is concluded that among the a-adrenergic receptors the az are those that predominantly regulate blood glucose levels. O n the other hand, the fact that yohimbine plus prazosin inhibit the hyperglycaemic properties of xylazine shows that a,-adrenergic receptors are also involved, but to a lesser extent, at least in ruminants.

Zusammenfassung Untersuchungen zur Rolle der a-adrenergen Rezeptoren

bei der Blutglucose-Regulation bei Schafen Die intravenose Injektion des a-Agonisten Xylazin (0,3 mg/kg KG) fiihrte bei Schafen zu einer

Hyperglykamie, die nach 30 min am ausgepragtesten war (1 10 mg/100 ml) und 3 Stunden lang signifikant war. Bei Verabreichung von Xylazin nach Vorbehandlung der Tiere mit dem a,-Blocker Prazosin (0,5 mg/kg i. v.) oder dem a2-Blocker Yohimbin (0,5 mg/kg i. v.) trat ebenfalls eine Hyper- glykamie auf, jedoch war der Blutglucose-Peak im Fall von Prazosin nicht hoher als 95 mg/100 ml, im Fall von Yohimbin sogar nur 70 mg/100 ml (Kontrollwert: 55 mg/100ml). Wurden die Tiere entweder mit Yohimbin und Prazosin oder dem a,- und a2-Blocker Tolazolin (3 mg/kg i. v.) vorbehandelt, so wurde der hyperglykamische Effekt von Xylazin unterdriickt. Diese Ergebnisse deuten darauf hin, datl bei der Regulation des Blutzuckerspiegels durch a-adrenerge Rezeptoren die a,-Rezeptoren die Hauptrolle spielen, die a,-Rezeptoren aber ebenfalls beteiligt sind.

References BROCKMAN, R. P., 1981: Effect of xylazine on plasma glucose, glucagon and insulin concentrations in

sheep. Res. Vet. Sci. 30, 383-384. EICHNER, R. D., R. L. PRIOR, and W. G . KUASNICKA, 1979: Xylazine-induced hyperglycaemia in

beef cattle. Am. J. Vet. Res. 40, 127-129. HAMPSHIRE, J., and N. ALTSZULER, 1981: Clonidine or xylazine as provocative tests for growth

hormone secretion in the dog. Am. J. Vet. Res. 42, 1073-1076. Hsu, W. H., and S. K. HUMMEL, 1981: Xylazine-induced hyperglycaemia in cattle: A possible

involvement of a,-adrenergic receptors regulating insulin release. Endocrinology 109, 825-829. NAICADATE, T., T. NAKAKI, T. MURAKI, and R. KATO, 1980 a: Adrenergic regulation of blood glucose

levels: Possible involvement of post-synaptic alpha-2 type adrenergic receptors regulating insulin release. J. Pharmacol. Exp. Ther. 215, 2 2 6 2 3 0 .

NAKADATE, T., T. NAKAKI, T. MURAKI, and R. KATO, 1980 b: Regulation of plasma insulin level by a,-adrenergic receptors. European J. Pharmacol. 65, 421-424.

SYMONDS, H. W., 1976: The effect of xylazine upon hepatic glucose production and blood flow rate in the lactating dairy cow. Vet. Rec. 99, 234-236.

SYMONDS, H. W., and C. B. MALLINSON, 1978: The effect of xylazine and xylazine followed by insulin on blood glucose and insulin in the dairy cow. Vet. Rec. 102, 27-29.