MDL 72222 (1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate) is a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones. In the present study, the sucrose-gap technique has been used to record depolarizing responses to 5-HT from the cells of the rabbit nodose and superior cervical ganglia and to investigate the potency and selectivity of MDL 72222 as an antagonist of these responses.
On nodose ganglia, responses to 5-HT were inhibited surmountably by MDL 72222 at concentrations up to 100 nmol/l. The threshold for antagonism was 2–10 nmol/l and the apparent pA2 value (Schild 1947) was 7.7±0.2,n=10. Blockade was selective since responses to GABA and noradrenaline were unaffected by MDL 72222, 100 nmol/l. With concentrations of MDL 7222 higher than 100 nmol/l, antagonism was concentration-related but not in a manner consistent with simple competitive antagonism and even a concentration of 1 μmol/l failed to abolish the response to 5-HT.
The results from the superior cervical ganglion were essentially similar to those obtained from the nodose ganglion. The threshold concentration of MDL 72222 for inhibition of 5-HT was 1–10 nmol/l and blockade was selective in that depolarizing responses to dimethylphenylpiperazinium (DMPP) was unaffected by a concentration of MDL 72222 of 1 μmol/l.
The data provide direct evidence that MDL 72222 is a potent and selective antagonist of the receptors for 5-HT which mediate depolarizing responses in vagal primary afferent cell bodies and in sympathetic ganglion cells.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Azami J, Fozard JR, Round AA, Wallis DI (1984) Selective blockade by MDL 72222 of the depolarizing action of 5-hydroxytryptamine on vagal primary afferents. Br J Pharmacol 81:129P
Donatsch P, Engel G, Richardson BP, Stadler P (1984a) ICS 205-930: A highly selective and potent antagonist at peripheral neuronal 5-hydroxytryptamine (5-HT) receptors. Br J Pharmacol 81:34P
Donatsch P, Engel P, Richardson BP, Stadler P (1984b) Subtypes of neuronal 5-hydroxytryptamine (5-HT) receptors as identified by competitive antagonists. Br J Pharmacol 81:33P
Fortune DH, Ireland SJ (1984) Antagonism by MDL 72222 of 5-HT-induced depolarisations of the rat isolated vagus nerve and superior cervical ganglion. Br J Pharmacol 81:170P
Fozard JR (1979) Blockade of receptors for 5-hydroxytryptamine on the sympathetic nerves of the rabbit heart. In: Langer SZ, Starke K, Dubocovich ML (eds) Advances in the biosciences. Pergamon, Oxford, pp 327–332
Fozard JR (1983) Differences between receptors for 5-hydroxytryptamine on autonomic neurones revealed by nor-(−)-cocaine. J Auton Pharmacol 3:21–26
Fozard JR (1984a) Neuronal 5-HT receptors in the periphery. Neuropharmacology (in press)
Fozard JR (1984b) MDL 72222: A potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 326:36–44
Fozard JR, Gittos MW (1983) Selective blockade of 5-hydroxytryptamine neuronal receptors by benzoic acid esters of tropine. Br J Pharmacol 80:511P
Fozard JR, Mwaluko GMP (1976) Mechanism of the indirect sympathomimetic effect of 5-hydroxytryptamine on the isolated heart of the rabbit. Br J Pharmacol 57:115–125
Fozard JR, Mobarok Ali ATM (1978) Blockade of neuronal tryptamine receptors by metoclopramide. Eur J Pharmacol 49:109–112
Fozard JR, Mobarok Ali ATM, Newgrosh G (1979) Blockade of serotonin receptors on autonomic neurones by (−)-cocaine and some related compounds. Eur J Pharmacol 59:195–210
Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol 12:323–328
Göthert M, Dührsen V (1979) Effects of 5-hydroxytryptamine and related compounds on the sympathetic nerves of the rabbit heart. Naunyn-Schmiedeberg's Arch Pharmacol 308:9–18
Higashi S, Nishi S (1982) 5-hydroxytryptamine receptors of visceral primary afferent neurones in rabbit nodose ganglia. J Physiol (Lond) 323:543–567
Higashi S, Ueda N, Nishi S, Gallagher JP, Shinnick-Gallagher P (1982) Chemoreceptors for serotonin (5-HT), acetylcholine (ACh), bradykinin (BK), histamine (H) and gammaaminobutyric acid (GABA) on rabbit visceral afferent neurons. Brain Res Bull 8:23–32
Ireland SJ, Fortune DH, Tyers MB (1983) Influence of 5-HT uptake on the 5-HT antagonist activity of metoclopramide on the rat superior cervical ganglion. Br J Pharmacol 78:68P
Kirby GC, McQueen DS (1984) Effects of the antagonist MDL 72222 and ketanserin on responses of cat carotid body chemoreceptors to 5-hydroxytryptamine. Br. J Pharmacol 83:259–269
Krayer O (1961) The history of the Bezold-Jarisch effect. Naunyn-Schmiedeberg's Arch Pharmacol 240:361–368
Lansdown MJR, Nash HL, Preston PR, Wallis DI, Williams RG (1980) Antagonism of 5-hydroxytryptamine receptors by quipazine. Br J Pharmacol 68:525–532
Nash HL, Wallis DI, Ash G (1984) 5-HT antagonists and blockade of neuronal (5-HT) receptors on ganglion cells. Gen Pharmacol, in press
Salmoiraghi GC, Page IH, McCubbin JW (1956) Cardiovascular and respiratory response to intravenous serotonin in rats. J Pharmac Exp Ther 118:477–481
Schild HO (1947) pA, a new scale for the measurement of drug antagonism. Br J Pharmac 2:189–206
Wallis DI (1981) Neuronal 5-hydroxytryptamine receptors outside the central nervous system. Life Sci 29:2345–2355
Wallis DI, Nash HL (1980) The action of methylated derivatives of 5-hydroxytryptamine at ganglionic receptors. Neuropharmacology 19:465–472
Wallis DI, North RA (1978) The action of 5-hydroxytryptamine on single neurones of the rabbit superior cervical ganglion. Neuropharmacology 17:1023–1028
Wallis DI, Woodward B (1975) Membrane potential changes induced by 5-hydroxytryptamine in the rabbit superior cervical ganglion. Br J Pharmac 55:199–212
Wallis DI, Lees GM, Kosterlitz HW (1975) Recording resting and action potentials by the sucrose-gap method. Comp Biochem Physiol 50C:199–216
Wallis DI, Stansfeld CE, Nash HL (1982) Depolarizing responses recorded from nodose ganglion cells of the rabbit evoked by 5-hydroxytryptamine and other substances. Neuropharmacology 21:31–40
About this article
Cite this article
Azami, J., Fozard, J.R., Round, A.A. et al. The depolarizing action of 5-hydroxytryptamine on rabbit vagal primary afferent and sympathetic neurones and its selective blockade by MDL 72222. Naunyn-Schmiedeberg's Arch. Pharmacol. 328, 423–429 (1985). https://doi.org/10.1007/BF00692911
- 5-HT receptors
- Sensory neurones
- Autonomic neurones
- MDL 72222
- Sucrose-gap method