Summary
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a new serotonin (5-HT) receptor agonist that binds selectively to the 5-HT1A binding site. In the present paper we investigated the cardiovascular effects of 8-OH-DPAT in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. The acute i.v. administration of 8-OH-DPAT (5–150Μg/kg) was in both rat strains associated with a biphasic blood pressure response and a bradycardia. The initial pressor response was due to a direct vascular effect of 8-OH-DPAT involving activation ofα-adrenoceptors since it was present in pithed rats and in reserpine pretreated rats and since it was attenuated by prazosin. The longer lasting hypotension was not due to a direct vascular relaxation or a presynaptic inhibition of transmitter release since the hypotension was not evident in pithed rats and since 8-OHDPAT did not influence the pressor responses to electrical stimulation in pithed rats. Rather, the combination of hypotension and bradycardia would suggest a central site of action although the intracerebroventricular (lat. ventricles) route of administration was not more efficient (to induce hypotension) than i.v. administration. At least the bradycardia was mediated by changes in vagal as well as sympathetic discharge since it was prevented by pretreatment with atropine and propranolol in combination but not by pretreatment with either agent alone. The cardiovascular effects of 8-OH-DPAT were not prevented by pretreatment with methergoline, methiothepin, pirenperone or cianserine or by 5-HT depletion by means of p-chlorophenylalanine, which suggests that the putative 5-HT receptor that is responsible for the hypotension and bradycardia to 8-OH-DPAT is not of a presynaptic type and does not have the pharmacological characteristics of a general 5-HT1 receptor.
Similar content being viewed by others
References
Baum, T., Shropshire, A. T.: Inhibition of efferent sympathetic nerve activity by 5-hydroxytryptophan and centrally administered 5-hydroxytryptamine. Neuropharmacology14, 227–233 (1975).
Bobillier, F., Seguin, S., Petitjean, P., Salvert, D., Touret, M., Jovet, M.: The raphe nuclei of the cat brain stem: A topographical atlas of their efferent projections as revealed by autoradiography. Brain Res.113, 449–486 (1976).
Clineschmidt, B. V., Lotti, V. J.: Indolamine antagonists: Relative potencies of inhibitors of tryptamine- and 5-hydroxytryptophan-evoked responses. Br. J. Pharmacol.50, 311–313 (1974).
Colpaert, F. C., Janssen, P. A. J.: The head-twitch response to intraperitoneal injection of 5-hydroxytryptophan in the rat; antagonist effects of a purported 5-hydroxytryptamine antagonist and of pirenperone, an LSD antagonist. Neuropharmacology22, 993–1000 (1983).
Engel, G., Göthert, M., Müller-Schweinitzer, E., Schlicker, E., Sistonen, L., Stadler, P. A.: Evidence for common pharmacological properties of (3H)5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autoreceptors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves. Naunyn-Schmiedeberg's Arch. Pharmacol.324, 116–124 (1983).
Fallon, S. L., Kim, H. S., Welch, J. J.: Electrophysiological evidence for modulation of dopamine neurons by 8-hydroxy-2-(di-n-propylamino) tetralin. Soc. Neurosci. Abstr.9, 716 (1984).
Fozard, J. R.: Functional correlates of 5-HT1 recognition sites. TIPS4, 288–289 (1983).
Fuxe, K., Agnati, L., Everitt, B.: Effects of methergoline on central monoamine neurons. Evidence for a selective blockade of central 5-HT receptors. Neurosci. Lett.1, 283–290 (1975).
Garcia-Sevilla, J. A., Ahtee, L., Magnusson, T., Carlsson, A.: Opiate-receptor mediated changes in monoamine synthesis in rat brain. J. Pharm. Pharmacol.30, 613–621 (1978).
Gerrito, F., Raiteri, M.: Serotonin release is modulated by presynaptic autoreceptors. Eur. J. Pharmacol.57, 427–430 (1979).
Gillespie, J. S., Muir, T. C.: A method of stimulating the complete sympathetic outflow from the spinal cord to the blood vessels in the pithed rat. Br. J. Pharmacol.30, 78–87 (1967).
Haeusler, G.: Clonidine-induced inhibition of sympathetic nerve activity. No indications for a central presynaptic or an indirect sympaticomimetic mode of action. Naunyn-Schmiedeberg's Arch. Pharmacol.286, 97–111 (1974).
Haigler, H. J., Aghajanian, G. K.: Peripheral serotonin antagonists: Failure to antagonize serotonin in brain areas receiving a prominent serotonergic input. J. Neural Transm.35, 257–273 (1974).
Hjorth, S., Carlsson, A., Lindberg, P., Sanchez, D., Wikström, H., Arvidsson, L.-E., Hacksell, U., Nilsson, J. L. G.: 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J. Neural Transm.55, 169–188 (1982).
Janssen, P. A. J.: Paul Janssen replies. TIPS4, 412 (1983).
Kalkman, H. O., Boddeke, H. W. G. M., Doods, H. N., Timmermans, P. B. M. W. M., van Zwieten, P. A.: Hypotensive activity of serotonin receptor agonists in rats is related to their affinity for 5-HT1 receptors. Eur. J. Pharmacol.91, 155–156 (1983).
Koe, B., Weissman, A.: P-Chlorophenylalanine: A specific depletor of brain serotonin. J. Pharmacol. Exp. Ther.154, 499–516 (1966).
Kuhn, D. M., Wolf, W. A., Lovenberg, W.: Review of the role of central serotonergic neuronal systems in blood pressure regulation. Hypertension2, 243–245 (1980).
Lalley, P. M.: Inhibition of phrenic and sympathetic vasomotor neurons in cats by the serotonin analogue 5-methoxy-dimethyltryptamine. J. Pharmacol. Exp. Ther.220, 39–48 (1982).
Leysen, J. E., Awouters, F., Kenis, L., Lauderon, J., Vandenberk, J., Janssen, P. A. J.: Receptor binding profile of R41468, a novel antagonist of 5-HT2 receptors. Life Sci.28, 1015–1022 (1981).
Lloyd, K. G., Bartholini, G.: The effect of methiothepin on cerebral monoamine neurons. In: Advances in Biochemical Psychopharmacology, Vol. 10, pp. 305–309. New York: Raven Press. 1974.
Marcinkiewicz, M., Verge, D., Gozlan, H., Pichat, L., Hamon, M.: Autoradiographic evidence for the heterogenity of the 5-HT1 sites in the rat brain. Brain Res.291, 159–163 (1984).
Martinez, A. A., Lokhandwala, M. F.: Evidence for a presynaptic inhibitory action of 5-hydroxytryptamine on sympathetic neurotransmission to the myocardium. Eur. J. Pharmacol.63, 303–311 (1980).
Martin, L. L., Sanders-Bush, E.: Comparison of the pharmacological characteristics of 5-HT1 and 5-HT2 binding sites with those of serotonin autoreceptors which modulate serotonin release. Naunyn-Schmiedeberg's Arch. Pharmacol.321, 165–170 (1982).
McCall, R. B., Humphrey, S. J.: Involvement of serotonin in the central regulation of blood pressue: Evidence for a facilitating effect on sympathetic nerve activity. J. Pharm. Exp. Ther.222, 94–102 (1982).
Middlemiss, D. N., Fozard, J. R.: 8-hydroxy-2-(di-n-propylamino)tetralin discriminates between subtypes of the 5-HT1 recognition sites. Eur. J. Pharmacol.90, 151–153 (1983).
Peroutka, S. J., Snyder, S. H.: Multiple serotonin receptors; differential binding of (3H) 5-hydroxytryptamine, (3H) lysergic acid diethylamine and (3H) spiroperidol. Molec. Pharmacol.16, 687–699 (1979).
Shipley, R. E., Tilden, J. H.: A pithed rat preparation suitable for assaying pressor substances. Proc. Soc. Exp. Biol. Med.64, 453–455 (1947).
Trolin, G.: Involvement of α-adrenergic receptors at different levels of the central nervous system in the regulation of blood pressure and heart rate. Acta Physiol. Scand. suppl. 430, 1975.
Van Nueten, J. M., Janssen, P. A. J., van Beek, J., Xhonneaux, R., Verbeuren, T. J., Vanhoutte, P. M.: Vascular effects of ketanserin (R41468), a novel antagonist of 5-HT2 serotonergic receptors. J. Pharmacol. Exp. Ther.218, 217–230 (1981).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gradin, K., Pettersson, A., Hedner, T. et al. Acute administration of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT-receptor agonist, causes a biphasic blood pressure response and a bradycardia in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. J. Neural Transmission 62, 305–319 (1985). https://doi.org/10.1007/BF01252244
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01252244