European Journal of Pharmacology, 184 (1990) 179-183 Elsevaer

179

EJP 20670

Short communication

Involvement of vasopressin in the cardiovascular effects of quinpirole Christine Damase-Mlchel

1, J e a n - L o u i s

M o n t a s t r u c 1, M a n e - A n t o i n e t t e T r a n :, C l a u d e G h a r l b 2, Gluslalne Geelen 2 and Paul Montastruc 1

t Laboratolre de Pharmacologte Mddzcale et Chmque, I N S E R M U317, Facult~ de M~decme, 37 Alldes Jules-Guesde, 31073 Toulouse C~dex, France and 2 Laboratolre de Phystologte, Facult~ de Mddecme Grange Blanche, 8 Avenue Rockfeller, 69373 Lyon C~dex, France Recetved 29 May 1990, accepted 5 June 1990

The effects of qumptrole, a specific dopanune D 2 receptor agomst, were investigated on cardxovascular responses and plasma levels of catecholamlnes and vasopressm m two groups of conscious dogs (1) control dogs and (2) dogs with chabetes mslpMus 0 e ammals surgically deprived of vasopressln) In normal dogs, i v qulnplrole (30 #g/kg) ehc~ted a decrease in blood pressure assocaated vath a nse m both plasma catecholamme and vasopressm levels In dogs with dmbetes mslptdus, i v qumplrole mduced a more marked decrease m blood pressure than m normal dogs Qumplrole did not change plasma noradrenalme and vasopressm levels m dogs with dmbetes mslpldus The present study demonstrates that the decrease m blood pressure ehclted by qumpxrole is assocmted with an mcrease m vasopressm release, wtuch counteracts the hypotenslve effect of the the dopanune D 2 receptor agomst Qtunplrole, [ArgS]vasopressm (AVP), Catecholamlnes, Dmbetes msxpldus, Blood pressure, Doparmne

1. Introduction The involvement of dopamlne D 2 receptors m the regulation of blood pressure has been discussed in the hterature (Montastruc et a l , 1990) However, recent studies using qmnp~role, a specific D 2 receptor agonlst, indicate that two mare mechamsms are involved m the hypotenslve acUon of qumplrole firstly, a peripheral depressor action ( m h l b m o n of noradrenerg~c neurotransmlss~on xaa D 2 receptors located at a presynapttc level a n d / o r autononuc gang,ha), and secondly, a central pressor component (revolving an increase m sympatheuc tone) The relatwe importance of these two components m a y vary according to the experimental condxtlons (anesthesm, species, route of

admlmstratxon), as suggested by N a g a h a m a et al (1987) m rats and Damase-Mxchel et al (m press) m dogs N a g a h a m a et al (1987) also suggested a role for vasopressm m the cardiovascular effects of qumplrole Tlus observation and the confhctmg results on the effects of D 2 agents on vasopressm release (Rack6 et a l , 1984, Ctuodera et a l , 1986) led us to compare the effects of qump:role on the cardxovascular responses as well as plasma catecholamlne and vasopressln levels in two groups of conscious dogs (1) normal control dogs and (2) dogs with diabetes mslp:dus

2. Materials and methods

2 1 Experimental protocol Correspondence to C Damase-Mlchel, Laborato~re de Pharmacologle M&hcale et Chmque, INSERM U317, Facult6 de M6decme, 37 All~es Jules-Guesde, 31073 Toulouse C&lex, France

The effect of qumplrole was examined m six conscious normal dogs (13-20 kg body weight) and stx conscious dogs with diabetes mslpldus (15-24

0014-2999/90/$03 50 © 1990 Elsewer Science Pubhshers B V (Biomedical Division)

180 kg body weight) The dose of qmnplrole (30 # g / k g ) was selected according to previous experiments (Damase-Mlchel et al, in press) After a stable blood pressure was obtained an at least after a 30 nun rest period, qulnplrole was injected i v as a bolus, and blood pressure and heart rate were recorded for an additional 60 man Plasma noradrenalme (NA) and adrenahne (A) concentrations were measured before and 5 nun after qumplrole injection, 1 e when the peak effect was observed Plasma arglmne vasopressln was assayed at the same ume

2 2 Surgical procedure Dogs were depnved of vasopressm by surgical lesion of the hypothalamo-neurohypophyslal system The general procedure for reducing chabetes mslpldus m dogs has been described before (Montastruc et a l , 1980) Briefly, under 1 v s o d m m t~opental anesthesm (12 5 m g / k g ) , the hypothalamus was reached after cutting away the soft palate and collapsing the bone along the sphenoethmoldal suture A cataract lancet was used to sectmn the supraoptlco-post-hypophysal tractus between the antehypophysls and the supraoptlc nuclei The aperture was then stopped with acryhc resin According to classical physmlogical notionS, Unne excretion ( + 2 - 6 1 daily according to the ammals, P < 0 05 m comparison with normal dogs) increased 15-20 days after surgery Ttus surgical procedure was performed several months (at least three) before the present study

parameters were always measured after a rest period of 30 man m conscious dogs

2 4 Biochemical assays Plasma vasopressm levels were assayed by radlolmmunoassay after extraction with bentonite according to the method of Skowsky et al (1974) using antiserum provided by Ked (Kell and Sovers, 1977) Plasma catecholanunes (NA and A) were measured by high pressure hquld chromatography with electrochemical (amperometnc) detection Briefly, fresh blood was collected (from a catheter introduced into the femoral artery 30 rain before m order to prevent stress) into tubes containing llttuum hepann w~th sodmm metablsulfite (10 M) and centrifuged 2000 × g 10 nun at 0 ° C Plasma was stored at - 8 0 ° C Catecholanunes were selectively isolated from the sample by adsorption onto activated alurmna, followed by elutlon with 0 1 M perchlonc acid Dlhydroxybenzylanune was used as internal standard to m o m t o r recovery from this extracuon step The worlong electrode potentml was set at 0 65 V against a A g / A g C I reference electrode Under these condlUons, the detecUon limit was 0 3 nM

2 5 Drug used Qmnplrole hydrochlonde (LY 171555, Ell Lilly and Company, Indlanapohs IN) was dissolved in sahne

2 6 Stattsttcal analysis 2 3 Cardtovascular parameters Several days before an experiment, the dogs were tramed to stand stdl for 3-4 h on a Pavlov table, and were accustomed to i v infusion and blood sampling procedures Systohc and dlastohc blood pressures were recorded by means of a catheter introduced into the a b d o m m a aorta vaa the left femoral artery under local anesthesia (xylocalne 5%) and connected to a Gould P231D transducer on one channel of a Honeywell recorder Heart rate was obtained using a heart period (pulse interval) meter triggered by the elect r o c a r d m g r a m (lead II) The cardmvascular

All data are presented as mean values + S E M Statistical analysis was performed with Wdcoxon test for paired comparisons or Mann-Whltney's test for unpaired comparisons The level of slgmflcance was P < 0 05

3. Results

3 1 Blood pressure and heart rate (fig 1) The resting values for dlastohc blood pressures and heart rate were similar in conscious normal

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dogs a n d dogs with diabetes m s i p t d u s A c u t e inj e c t i o n of qulnpxrole (30 t~g/kg i v ) i n d u c e d a decrease i n b l o o d pressure m b o t h groups T h e depressor response observed was slgmflcantly more p r o n o u n c e d i n dogs with diabetes msxpldus t h a n i n n o r m a l dogs ( - 4 8 3% m dogs with diabetes m s l p l d u s versus - 2 5 % i n n o r m a l dogs for systohc b l o o d pressure 5 m l n after q u m p l r o l e m jecUon, P < 0 05) Moreover, q u m p l r o l e ehclted a s i g m h c a n t increase in heart rate, the m a g m t u d e of which was similar i n the two groups of a m m a l s ( + 130%, 5 m m after injection)

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0 NORMAL 1)1 Fig 1 Effect of i v adnumstratlon of qmnptrole (30 #g/kg) to conscious normal control dogs (n = 6) and conscaous dogs with diabetes msipldus (DI, n = 6) on blood pressure (upper pannel, mm Hg) and heart rate (lower pannel, beats/nun) measured before (open columns) and 5 mm after (sohd columns) qulnplrole mjection Statistical analysis was done with the Wilcoxon test for paared comparisons Mean values are given Vertical lines show S E M * P < 0 05 when compared vath pretreatment values

NORMAL DI Fig 2 Effect of 1v adnumstration of qmnplrole (30 #g/kg) to consoous normal control dogs (n = 6) and conscious dogs with diabetes lnslpldus (DI, n = 6) on noradrenalme (upper pannel, nmol/l), adrenahne (freddie panel, nmol/l) and argmme vasopressm (lower pannel, pg/ml) plasma levels measured before (open columns) and 5 nun after (sohd columns) qmnplrole rejection Statistical analysis was done with the Wilcoxon test for paired comparisons Mean values are given Vertical lines show S E M * P < 0 05 when compared with pretreatment values

m l n after q u l n p l r o l e lnjecUon, l e w h e n the cardiovascular p a r a m e t e r s h a d reached peak values I n dogs with chabetes mslpldus, p l a s m a N A levels were n o t s i g n i f i c a n t l y m o d i f i e d after qumptrole, whereas p l a s m a A levels were d r a m a t l -

182 cally Increased (15 7-fold basal values), plasma vasopressln (wtuch is very low under resting condltions) did not change in these ammals after qulnplrole

4. Discussion The present study with consoous dogs indicates that 1 v adlmmstratlon of qumpirole reduces a more marked decrease m blood pressure in dogs with diabetes mslpldus (1 e ammals deprtved of vasopressxn) than m normal dogs Moreover, the specific D 2 receptor agomst increased vasopressm plasma levels m normal dogs Taken together, these results suggest the involvement of vasopressm in the changes in blood pressure observed after quinpirole They clearly demonstrate that acute adnumstratlon of qulnplrole in normal dogs is associated with a rise in vasopressln release, which counteracts the hypotenslve action of the 3 2 agomst This observation explams the more marked decrease in blood pressure observed after qumplrole in dogs with diabetes lnsxpldus The rise in vasopressm plasma levels requires comment Firstly, the rise is not of a baroreflex orlgm but probably results from central activation in fact, an effect through baroreflex pathways can be ruled out since we have found previously that quinplrole still induces an increase in vasopressin plasma levels m smoaortlc denervated dogs (l e ammals deprived of baroreflex pathways) Thus, a central mechanism can be hypothetmed since central admlmstranon of qumplrole at doses ineffective by peripheral route induces an increase in vasopressm levels In conscious dogs (Damase-Mmhel et al, in press) Secondly, the results suggest the involvement of D 2 receptors in the increase in vasopressin levels Confhcting results about the involvement of these receptors have been reported in the hterature For instance, N a g a h a m a et al (1987) described an increase in vasopressln plasma levels after quinplrole injection in rats, and morphologmal studies indicate that doparmnergm neurons terminate in the supraoptic nucleus, mechum eminence and the neural lobe of the posterior pituitary (Zaborsky et al, 1975) In contrast, the data of Chtodera et al (1986) show that metoclopramIde increases

vasopressin release in humans This last conflicting result can be explmned by the lack of selectivity of metoclopralmde, which is a doparmne D 1 / D 2 receptor antagomst The increase in vasopressin in normal dogs is associated with a rise in plasma noradrenahne and adrenaline as a result of both baroreflex and central activation of sympathetic pathways (Damase-Mlchel, in press) The rise in noradrenahne plasma levels was not found in dogs with diabetes lnslpidus Thus, it is hkely that vasopressm partlcipates in elevating noradrenallne plasma levels by Increasing sympathetic tone, as suggested by Share (1988) This observation explains why qulnplrole failed to increase noradrenahne levels in dogs with diabetes msipldus We observed that, after qumpirole, adrenahne plasma levels were surprisingly increased in dogs with diabetes lnSlpldus We suggest that the dramatic decrease in blood pressure ehcIted by qumplrole in dogs with diabetes mslpidus stimulates adrenaline release from the adrenal medulla In conclusion, the present study demonstrates the involvement of vasopressln release in the cardiovascular effects of qulnplrole, thus supportlng the hypothesis that D 2 dopanunergm pathways are involved in the central regulation of vasopressin release This action can in part counteract the decrease in blood pressure induced by the dopamine D 2 receptor agomst Lastly, from a therapeutic point of wew, one can stress that the qmnplrole-mduced increase in vasopressln release can buffer the peripheral hypotensive action of qulnpirole This property does not appear to favour the use of this class of compound as antihypertensive agents

Acknowledgements The authors acknowledge the generous gift of qumplrole by Eh-Lllly Company, Mrs Portolan and Mr Bernou for techmcal help and Mrs Bontemps for the preparaUon of the manuscript

References Cluodera, P, R Volpt, R Delslgnore, C Marchest, G Salata, L Catmnelll, G Ross1and V Colro, 1986, Different effects

183 of metoclopranude and dompendone on arglmne-vasopressm secretion m man, Br J Clm Pharmacol 22, 479 Damase-Mlchel, C , J L Montastruc, C Ghanb, G Geelen, G de Samt-Blanquat and M A Tran, Effect of qmnplrole, a specafic dopamme DA2 receptor agomst on the sympathoadrenal system m dogs, J Pharmacol Exp Ther 252, (m press) Ked, L C and N B Sovers, 1977, Reducuon m plasma vasopressm levels of deshydrated rats following acute stress, Endocnnology 100, 30 Montastruc, J L , C Damase-Mlchel and P Montastruc, 1990, Dopamme and hypertension, m Peripheral Doparmne Pathophyslology, ed F Amenta (CRC Press, Boca Raton, FL) p 163 Montastruc, J L , L Dang-Tran, J R Castdlo-Ferrando, F Morales-Ohvas, G Gadlard-Plaza and P Montastruc, 1980, Effects of yohtmbme and prazosm on water balance m dogs with diabetes mslpldus, J Pharmacol (Pans) 11, 441 Nagahama, S, H S Ann, Y Chen, M D Lmhetmer and S

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