Antagonism of dopamine-induced chemosensory inhibition by ergot alkaloids

Neuroscience Letters, 8 (1978) 131--136

131

© Elsevier/North-Holland Scientific Publishers Ltd.

ANTAGONISM OF DOPAMINE-INDUCED CHEMOSENSORY INHIBITION BY ERGOT ALKALOIDS PATRICIO ZAPATA and CAROLINA LARRAIN

Laboratory of Neurobiology, Catholic University, Santiago (Chile) (Received January 23rd, 1978) (Accepted January 31st, 1978)

SUMMARY

Intracarotid and i.v. injections of ergometrine, methylergometrine, ergotamine, dihydroergotamine, dihydroergotoxine and 2-Br~-ergocryptJine depressed the frequency of chemosensory impulses, recorded from the carotid nerve of anesthetized cats. After administration of ergot alkaloids, dopamine-induced inhibition of chemosensory activity was blocked; this effect was not associated with blocking of a-adrenoceptors for ergometrine, methylergometrine, ergotamine ana 2-Br~ ~rgocryptine, but it coincided with a-adrenergic antagonism for dihydroergotamine and dihydroergotoxine. It is concluded that ergot alkaloids can act on carotid body chemoreceptors as dopamine analogues and antagonists.

Ergot alkaloids have been used for a long time as a-adrenoceptor blocking agents. "l~nus,when dihydroergotamine was found to antagonize the inhibition of carotid body chemosensory activity by dopamine (DA), it was suggested that DA effects on carotid body. chemorecept~)rs were mediated through aadrenoceptors [8]. However, DA is the predominant catecholamine in carotid body tissues [ 14], and the assay of several DA analogues and antagonists [ 5] and that the adrenoceptor stimulating and blocking agents [6] on carotid body preparations suggest that chemosensory inhibition is mediated by specific 'dopaminoceptors'. This prompted us to study the effects of ergot alkaloids on chemosensory activity. Experiments were performed in pentobarbitone-anesthetized cats. Both carotid nerves were sectioned at their junctions with the glossoph~sxyngeal nerves and one of them prepared for electrophysiologicalrecording of its impulse activity.To exclude barosensory and sympathetic discharges,a crush was made between the carotid body and sinus and the ganglio~lomerular nerves were ~tion~. Action potentials were recorded on an F M tape recorder ( f r e q u ~ y response, dc-1250 Hz)' On-line and later analysisof chemosensory ~ u e n c y changes were peffozrned with an electronic counter coupled to a digitlfl.analogconverter (or to a digitalprinter).Systemic azterialpressure,

132

ventilation and rectal ~mperature were monitored. Dmt~s were administered either i.v. through a catheter introduced into ~he saphenous vein or by intracarotid (i,e.) injections given through a short tubing introduced retro~adely into the thyroid artery. Chemosensory inhibition was observed as the first response to i.e. or i.v. injections of ergometrine, methylergometrine, ergotamine, dihydroergotamine, dihydroergotoxine and 2-Br~.ergoerypine (Fig. 1, left side). The decreases in frequency -although usually not attaining complete inhibition- are more prolonged than those evoked by doses of DA that induced fun inhibition of chemosensory activity. After disappearance of the depression induced by these initial injections of ergots, ehemosensory frequency increased moderately for the rest of the experiment. Depending on the doses, a second or further injections of the alkaloids provoked either no changes, biphasie responses (slow rebound after fast inhibition) or increases in ehemosensory frequency (Fig. 1, right side). Fig. 2 illustrates the results obtained in five different preparations, to which ergometrine, methylergometrine, ergotamine, dihydroergotamine and dihydroergotoxine were applied. The curves on the left column indicate that an these

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134 compounds displaced to the right the dose-response curves for chemosensory inhibition induced by DA. However, in other experiments (not illustrated) in which larger doses of ergots were applied, an unsunnountable block of DAelicited chemosensory inhibition was produced, and large doses of DA resulted in chemosensory excitation. The right column presents the dose-response curves for the effects of i.v. injections of noradrenatine upon systemic arterial pressure, in the same preparations. Doses of ergometrine, methylergometrine and ergotamine which blocked DA effects on carotid body (Fig. 2a,c,e) did not antagonize the systemic pressor effects of nomdrenaline (Fig. 2d,f); moreover, the effects of large doses were potentiated. However, doses of dihydroergotamine and dihydroergotoxine which antagonized DA effects on the carotid body (Fig. 2g,i), produced a concomitant reduction of noradrenaline effects on the systemic arterial pressure (Fig. 2hj). These observations are in line with the classical description that d~ydrogenated alkaloids have ~-adrenergic blocking properties, while amine alkaloids do not [4]. Thus, dopaminergic block by ergot alkaloids in the carotid body can be induced in the absence of a-adrenergic block in the systemic circulation. 2-Br~-ergocryptine is considered a specific and long-lasting stimulant of dopaminoceptors ~7,10]. Applied in low doses (25--50/~g • kg -1 i.v.) produced a displacement to the right of dose-response curves for DA-elicited chemosensory inhibition. However, cumulative doses of 100/~g • kg -~ or more resulted in complete blockade of DA-elicited inhibition and its reversal into chemosensory excitation (Fig. 3a). This was associated with full block of DAinduced hypotension and potentiation of hypertensive responses (Fig. 3b), without concomitant a-adrenergic blockade (Fig. 3c). The present results suggest that ergot alkaloids can operate in the carotid body as D A analo~;ues and antagonists. The blocking action of dihydroergotamine upon DA-induced chemosensory inhibition [10] does not imply that it is due to itsa-adrenergic blocking activity. Furthermore, a-adrenoceptor stimulants do not elicitchemo~ensory inhibition [6,13], while haloalkylamines do not interfere with DA-induced chemosensory inhibition, unless they reduce blood pressure below the criticalclosing pressure of carotid body vessels [6 ]. Our findings that e~nt. alkaloids can mimic D A effects on the carotid body, confirm several recent reports on the agonistic activity of ergots on dopaminoceptors. Thus, ergometrine, methylergometrine and 2-Br-a-ergocryptine induced stereotyped behaviour [7], hypothermia [7], rotation after unilateral nigrostriatallesions by 6-OH-Doparnine [12] and increased c A M P in retina [10]. These effects are similar to those of apomorphine, a well-known D A analogue, and they are antagonized by butyrophenones or phenothiazines. The present observation that ergot~ can block D A effects in the carotid body is also confirmatory of their antagonism in other tissues.DA-induced inhibition in snail ganglia is antagonized by ergometrine, ergotamine, dihydroergotamine m~d dihydroergotoxine [11]. Ergometrine reduces DA-induced increase in canine renal blood flow [2]. Dopaminergic agonist and antagonistic effects of ergots here reported have

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also been found in ganglia of Aplysia, where the blocking action of ergometrine and methylergometrine on DA inhibitory effects (leaving also imtact DA excitatory effects) were preceded by transient hyperpolarization [1]. Ergometrine also stimulated DA-sensitive adenylate cyclase of striatal homogenares, but reduced DA-stimulation of the enzyme [9]. Finally, in studies in which [3H] haloperidol and [3H]dopamine showed high affinity binding to membranes from limbic and striatal areas, several ergots manifested substanti~ affinity for both types of binding [ 3]. ACKNOWLEDGEMENTS

This work was supported by the Gildemeister Foundation and by granl 211/75 from the Catholic University Research Fund. Ergot derivatives were kindly supplied by Sandoz Pharmaceutica. Thanks are due to Prof. C. Eyzaguirre, Department of Physiolof,-y, University of Utah, for reviewing the manuscript. REFERENCES 1 Ascher, P., InhibitQry and excitatory effects of dopamine on Aplysia neurones, J. Physiol. (Lond.), 225 (1972) 173--209. 2 Bell, C., Conway, E.L. and Lang, W.J., Ergometrine and apomorphine as selective

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3 4 5 6 7 8 9 10 11 12 13 14

antagonists of dopamine in the canine renal vasculature, Brit. J. Pharmacol., 52 (1974) 591--595. Burr, D.R., Creese, I. and Snyder, S.H., Properties of [SH]haloperido| and [3H]dopamine binding associated with dopamine receptors in calf brain membranes, Molec. Pharmacol., 12 (1976) 800--812. Goodman, L.J. and Gilman, A., The pharmacological basis of therapeutics, 5th edn., MacMillan, N.Y., 1975, p. 87¢~ Llados, F. and Zapata, P., Effects of dopan~ine analogues and antagonists on carotid body chemosensors in situ, J. Physiol. (Lond.), 274 (1978) in p n ~ . Llados, F. and Zapata, P., Effects of adrenoceptor stimulating and blocking agents on carotid body chemosensory inhibition. J. Physiol. (Lond.), 274 (1978) in press. Puech, A.J., Simson, P., Chermat, R. and Boissier, J.-R., Bromocriptine and methylergometrine: pharmacological approach of the mechanism of their central effects, Pharmacol. Res. Commun., 9 (1977) 299--306. Sampson, S.R., Aminoff, M.J., Jaffe, R.A. and Vidruk, E.H., A pharmacological analysis of neurally induced inhibition of carotid body chemoreceptors activity, J. Pharmacol. exp. Ther., 197 (1976) 119--125. • Schmidt, M.J. and Hill, L.E., Effects of ergots on adenylate cyclase activity in the corpus striatum and pituitary, Life Sci., 20 (1977) 789--798. Schorderet, M., Direct evidence for the stimulation of rabbit retina dopamine receptors by ergot alkaloids, Neuroscience Letters, 2 (1976) 87--91. Struyker-Boudier, H.A.J., Gielen, W., Cools, A.R. and Van Rossum, J.M. Pharmacological analysis of dopamine-induced inhibition and excitation of neurones of the snail Helix aspersa, Arch. int. Pharmacodyn., 209 (1974) 324--331. Woodruff, G.N., Elkhawad, A.O. and Crossman, A.R., Further evidence for the stimulation of rat brain dopamine receptors by ergometrine, J. Pharm. Pharmacol., 26 (1974) 455--456. Zapata, P., Effects of dopamine on carotid chemo- and baro-receptors in vitro, J. Physiol. (Lond.), 244 (1975) 235--251. Zapata, P., Hess, A., Bliss, E.L. and Eyzaguirre, C., Chemical, electron microscopic and physiolozical observations on the role of catecholamines in the carotid body, Brain Res., 14 (1969) 473--496.