The CCKA receptor antagonist devazepide inhibits the effect of apomorphine on vasopressin release in pigs

The CCKA receptor antagonist devazepide inhibits the effect of apomorphine on vasopressin release in pigs

Pergamon Gen. Pharmac.Vol. 25, No. 7, pp. 1337-1340, 1994 Copyright© 1994ElsevierScienceLtd Printed in Great Britain.All rights reserved 0306-3623/94...

283KB Sizes 0 Downloads 52 Views

Pergamon

Gen. Pharmac.Vol. 25, No. 7, pp. 1337-1340, 1994 Copyright© 1994ElsevierScienceLtd Printed in Great Britain.All rights reserved 0306-3623/94 $7.00+ 0.00

0306-3623(94)E0108-X

The C C K A Receptor Antagonist Devazepide Inhibits the Effect of Apomorphine on Vasopressin Release in Pigs R. F. P A R R O T T ~ a n d M. L. F O R S L I N G 2 tAFRC Babraham Institute, Cambridge CB2 4AT [Tel: 0223 832312; Fax: 0223 837759] and 2UMDS, St Thomas' Hospital, London SEI 7EH, England (Received 24 February 1994)

Abstract--1. A transient increase in plasma vasopressin concentrations represents a physiological correlate of nausea in animals that vomit. 2. The CCK^ receptor antagonist devazepide has previously been shown to inhibit vasopressin release induced in pigs by intravenous (i.v.) CCK. 3. This study investigated whether devazepide (70/zg/kg i.v.) would affect vasopressin secretion induced in pigs (n = 6) by the emetic drug apomorphine (25 #g/kg i.v.). 4. Apomorphine stirfiulated vasopressin release in the 30 min period following injection; this effect was prevented by prior administration of devazepide. 5. The results suggest that CCK^ receptor antagonists may have the ability to prevent nausea and/or emesis.

Key Words: Nausea and emesis, vasopressin, cholecystokinin, devazepide, apomorphine

INTRODUCTION In animals that vomit, nausea-inducing stimuli provoke the release of vasopressin. For example, simulated motion sickness (Koch et al., 1990), cytotoxic drugs (Edwards et al., 1989), apomorphine (Rowe et al., 1979) and the emetic peptide cholecystokinin (CCK; Miaskiewicz et al., 1989) all have this effect in man. Similarly, i.v. injected CCK (Parrott et al., 1991a, b) and apomorphine (Parrott et al., 1991b) increase concentrations of lysine vasopressin (LVP) in pigs. Moreover, the LVP response of pigs to CCK is blocked by pre-treatment with a CCK^ (devazepide), but not a CCK a, receptor antagonist (Parrott and Forsling, 1992). Central CCK 'A' receptors are found almost exclusively in the region of the brainstem area postrema and the adjacent nucleus tractus solitarius (AP/NTS; Hill and Woodruff, 1990), a site well-known for its role in the control of emesis (Wang and Borison, 1952). Moreover, the observation that CCK activates c-los expression in the AP/NTS (Fraser and Davison, 1992) by CCK A receptor action (Fraser and Davison,

1993) suggests that this region may mediate the nauseogenic actions of exogenous CCK. However, because metoclopramide inhibits CCK-induced LVP release in pigs (Parrott et al., 1991b), the neuroendocrine actions of CCK, like those of apomorphine (Stefanini and Clement-Cormier, 1981), may also involve dopaminergic pathways. Conversely, if CCKA and dopamine receptors in the AP/NTS both have a role in the control of nausea and emesis, then devazepide might alter LVP secretion in pigs treated with apomorphine. The objective of the present experiment was to test this hypothesis.

MATERIALS AND M E T H O D S Animals

Six Large White breed prepubertal pigs weighing approximately 25 kg at the start of the study were used. They were housed in individual metabolism cages, fed twice daily with water available ad libitum, weighed regularly and adapted to regular handling.

1337

1338

R.F. PARROTTand M. L. FORSLING

Surgery The pigs were anaesthetized with closed circuit halothane and surgically prepared, using sterile precautions, with a catheter in the external jugular vein. The catheters passed through the body wall in the neck region were protected with adhesive bandages. They were kept patent by regular flushing with sterile heparinized saline.

Experimental procedure The experimental treatments (devazepide + vehicle, vehicle + apomorphine, devazepide + apomorphine) were given by i.v. injection to three animals at the same time on each day of testing. This procedure was repeated until all the pigs had received each treatment combination. Blood samples (10 ml) for hormone analysis were collected before devazepide or vehicle injection (time A; - 1 0 m i n ) and 2, 5, 10, 20 and 30min after apomorphine or vehicle injection (time B; 0min). Plasma obtained by centrifugation was stored at 30°C. -

described (Parrott and Forsling, 1992). Apomorphine hydrochloride (25/~g/kg; Sigma Chemical Co. Ltd, St Louis, MO, U.S.A.) was freshly prepared each day in saline containing ascorbic acid (0.2 mg/ml) as an anti-oxidant.

Hormone measurement Plasma concentrations of LVP and cortisol were analysed by radioimmunoassay using previously described methodology (Parrott and Forsling, 1992; Parrott and Goode, 1992, respectively).

Statistical analysis Treatment effects were examined by an analysis of variance of logarithmically transformed data which calculated the net change in the area under the response curve (Parrott and Goode, 1992). Results were compared for the pre-treatment ( - 1 0 m i n ) , early (0-9 min) and later (10 30 min) post-treatment periods. Significant differences are given as two-tailed probability values.

-

RESULTS

Drugs used Devazepide (70 pg/kg) was made up in dimethylsulphoxide and propylene glycol, as previously 9

--

The effects of the treatments on plasma LVP concentrations are illustrated in Fig, 1. No differences were detected between treatment groups in blood

TIME A TIME B [] DEVAZEPIDE + VEHICLE [] VEHICLE + APOMORPHINE • DEVAZEPIDE + APOMORPHINE T

LVP (pmolll)

l i

0

~, A

A -10

B

2

5

10 TIME

20

30

(rain)

Fig. 1. Changes in plasma lysine vasopressin (LVP) concentrations (mean ___SEM; pmol/1) in pigs (n = 6) following i.v. administration of devazepide (70/~g/kg; time A; - 10 min), +vehicle (time B; 0 rain), vehicle (time A) +apomorphine (25 #g/kg; time B) or devazepide (time A) +apomorphine (time B). There were no significant differences between treatment groups before time B or between vehicle+ devazepide and devazepide + apomorphine treatments after time B. However, LVP concentrations were significantly increased after time B when the pigs received vehicle+ apomorphine (see text for details).

Effect of devazepide on vasopressin release in pigs samples taken at - 10 min. Similarly, hormone levels did not differ in either part of the post-treatment period following injection of devazepide (time A) + vehicle (time B) or devazepide (time A ) + apomorphine (time B). By contrast, when the pigs received vehicle (time A) + apomorphine (time B), LVP concentrations were higher than those seen after treatment with devazepide + vehicle (P < 0.005) or devazepide + apomorphine (P < 0.004) in the early and also in the later (devazepide + vehicle, P < 0.001; devazepide + apomorphine, P < 0.05) post-treatment periods. The animals became agitated, and one vomited, when treated with vehicle + apomorphine whereas their behaviour was normal when they received devazepide with, or without, apomorphine. However, the stimulatory effect of apomorphine on cortisol secretion (Parrott et al., 1991b) was not significantly reduced by prior administration of devazepide (data not shown). DISCUSSION It has previously been demonstrated that the CCK A receptor antagonist devazepide, but not the CCK B receptor antagonist L365,260, will inhibit LVP release induced in pigs by i.v. injections of CCK (Parrott and Forsling, 1992). The present results further show that devazepide will antagonize the LVP response of pigs to the emetic dopaminergic agonist apomorphine. Although the effects of devazepide on endocrine function in apomorphine-treated animals have not been described before, devazepide has been used in an attempt to reverse the inhibitory effects of CCK and apomorphine on food intake in rats (Bednar et al., 1991). In that study, the drug (57 #g/kg i.p.), produced a significant (P < 0.05) increase (111%) in feeding in CCK-treated rats and a non-significant increase (67%) in apomorphine-treated animals. By contrast, the CCKB antagonist L365,260, given at the same dose, either had no effect (after CCK) or resulted in a 19% decrease (after apomorphine). Therefore, it is conceivable that had devazepide been given at a higher dose or by a different route, as in the present study, it also might have antagonized the behavioural effects of apomorphine. The transient increase in vasopressin secretion that occurs in response to a noxious agent is considered to represent a physiological correlate of nausea in animals that are able to vomit (Parrott and Forsling, 1992). Hence, the ability of devazepide to inhibit this response, whether induced by CCK or apomorphine, raises interesting questions about the physiological role of CCKA receptors. Since CCK cannot cross the blood-brain barrier (Passaro et al., 1991), access to

1339

central tissues can only be gained via circumventricular organs such as the area postrema. Moreover, due to the high density of CCK^ receptors in this region it might be hypothesized that, under certain abnormal conditions, CCK levels in the circulation can rise sufficiently to act on these receptors and trigger an emetic response. However, although apomorphine is known to produce large increases in circulating concentrations of pancreatic polypeptide (Feldman et al., 1988) the possibility that emetic agents may substantially enhance endogenous CCK release has not been investigated. The parallels between the effects of apomorphine, which acts on dopamine receptors in the AP/NTS to induce emesis (Stefanini and ClementCormier, 1981), and those of CCK are striking. For example, dopamine antagonists inhibit the effects of both CCK and apomorphine on feeding in rats (Bednar et al., 1991) and of CCK on LVP release in pigs (Parrott et al., 1991b) and the CCK^ antagonist devazepide prevents the LVP, but not the cortisol, response of pigs to both CCK (Parrott and Forsling, 1992) and apomorphine. Therefore, there is reason to suppose that, as previously also suggested in relation to food intake (Bednar et al., 1991), CCK and dopamine together may also play a role in the control of nausea and emesis. In conclusion, the ability of devazepide to inhibit the LVP response of pigs to apomorphine indicates that CCK A receptor antagonists might have potential as new types of therapeutic agents for the alleviation of nausea and emesis. Acknowledgements--The authors are grateful to Dr M. M.

Traub, Merck, Sharp and Dohme Research Laboratories, Harlow, U.K. for supplying devazepide and to Mr D. Brown for carrying out the statistical analysis.

REFERENCES Bcdnar I., Forsberg G., Linden A., Qureshi G. A. and S6dersten P. (1991) Involvement of dopamine in inhibition of food intake by cholecystokinin octapeptide in male rats. J. Neuroendocr. 3, 491-496. Edwards C. M., Carmichael J., Baylis P. H. and Harris A. L. (1989) Arginine vasopressin--a mediator of chemotherapy induced emesis? Br. J. Cancer 59, 467-470. Feldman M., Samson M. W. K. and D'Orisio T. M. (1988) Apomorphine-induced nausea in humans: release of vasopressin and pancreatic polypeptide. Gasteroenterology 95, 721-726. Fraser K. A. and Davison J. S. (1992) Cholecystokinininduced c-fos expression in the brain stem is influenced by vagal nerve integrity. Expl Physiol. 77, 225-228. Fraser K. A. and Davison J. S. (1993) Meal-induced c-fos expession in brain stem is not dependent on cholecystokinin release. Am. J. Physiol. 265, R235-239. Hill D. R. and Woodruff G. N. (1990) Differentiation of central cholecystokinin receptor binding sites using the non-peptide antagonists MK-329 and L365,260. Brain Res. 526, 276-283.

1340

R.F. PARROTT and M. L. FORSLING

Koch K. L., Summy-Long J., Bingaman S., Sperry N. and Stern R. M. (1990) Vasopressin and oxytocin responses to illusory self-motion and nausea in man. J. Clin. Endocr. Metab. 71, 1269-1275. Miaskiewicz S. L., Stricker E. M. and Verbalis J. G. (1989) Neurohypophyseal secretion in response to eholecystokinin but not meal-induced gastric distension in humans. J. Clin. Endocr. Metab. 68, 837-843. Parrott R. F. and Forsling M. L. (1992) CCK-A receptors mediate the effect of cholecystokinin on vasopressin but not on cortisol in pigs. Am. J. Physiol. 262, RI 154-R1157. Parrott R. F. and Goode J. A. (1992) Effects of intracerebroventricularly corticotropin-releasing hormone and intravenous morphine on cortisol, prolactin and growth hormone in sheep. Dom. Anita. Endocr. 9, 141-149. Parrott R. F., Ebenezer I. S., Baldwin B. A. and Forsling M. L. (1991a) Central and peripheral doses of cholecystokinin that inhibit feeding in pigs also stimulate vasopressin and cortisol release. Expl. Physiol. 76, 525-531. Parrott R. F., Ebenezer I. S., Baldwin B. A. and Forsling M. L. (1991b) Hormonal effects of apomorphine and

cholecystokinin in pigs: modification of the response to choleeystokinin by a dopamine antagonist (metoclopramide) and a kappa opioid agonist (PD117301). Acta Endocr. 125, 420-426. Passaro E., Debas M., Oldendorf W. and Yamada Y. (1991) Rapid appearance of intraventricularly administered neuropeptides in the peripheral circulation. Brain Res. 348, 315-317. Rowe J. W., Shelton R. L., Helderman J.M., Vestal R. F. and Robertson J. L. (1979) Influence of the emetic reflex on vasopressin release in man. Kidney Int. 16, 729-735. Stefanini E. and Clement-Cormier Y. (1981) Detection and characterization of dopamine receptors in dog area postrema. In Apomorphine and Other Dopaminominetics. Vol. 2: Clinical Pharmacology (Edited by Corsini G. V. and Gessa G. L.), pp. 297-301. Raven Press, New York. Wang S. C. and Borison M. L. (1952) A new concept of organization of the central emetic mechanisms: recent studies on the site of action of apomorphine copper sulphate and cardiac glycosides. Gasteroenterology 22, 1-12.