Summary
Adrenergic mechanisms were analysed in the pithed rat to determine to what extent the actions of drugs observed in vitro are relevant in situ.
The drugs examined were those which are known to block the neuronal or extraneuronal uptake of noradrenaline (cocaine, desipramine and corticosterone) or to be antagonists at post and/or pre-junctional α-adrenoceptors (prazosin and yohimbine) together with the antidepressant, mianserin, which has been implicated in several of these actions. These drugs were tested against the arterial diastolic pressor, cardiac chronotropic and vas deferens responses to sympathetic nerve stimulation, to indirect sympathomimetics or to direct sympathomimetics, which were chosen according to whether they were substrates for noradrenaline uptake processes or selective between adrenoceptors.
Pressor and cardiac responses to sympathetic nerve stimulation or to intravenous noradrenaline were potentiated by blockade of neuronal uptake but only the pressor effect of noradrenaline was potentiated by blockade of extraneuronal uptake. The effects of the antagonists suggested that the pressor effects of noradrenaline and of sympathetic nerve stimulation result from a combination of activation of α1- and α2-adrenoceptors, but that the effect of noradrenaline had a relatively greater contribution from the α2-adrenoceptors. Mianserin was found to potentiate adrenergic responses at low doses, to produce limited antagonism at post-junctional α1-adrenoceptors in high doses but to have no detectable effect at postjunctional α2-adrenoceptors.
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References
Autret, A. M., Schmitt, H., Fenard, S., Petillot, N.: Comparison of haemodynamic effects of α-sympathomimetic drugs. Eur. J. Pharmacol. 13, 208–217 (1971)
Baumann, P. A., Maitre, L.: Blockade of presynaptic α-receptors and of amine uptake in the rat brain by the antidepressant mianserine. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 31–37 (1977)
Bell, C., Kushinsky, R.: Involvement of Uptake1 and Uptake2 in terminating the cardiovascular activity of noradrenaline in normotensive and genetically hypertensive rats. J. Physiol. (Lond.) 283, 41–51 (1978)
Borowski, E., Starke, K., Ehrl, H., Endo, T.: A comparison of preand postsynaptic effects of α-adrenolytic drugs in the pulmonary artery of the rabbit. Neuroscience 2, 285–296 (1977)
Brown, C. M., McGrath, J. C., Summers, R. J.: The effects of α-adrenoceptor agonists and antagonists on responses of transmurally stimulated prostatic and epididymal portions of the isolated vas deferens of the rat. Br. J. Pharmacol. 66, 553–564 (1979)
Cavero, I., Gomeni, R., Lefevre-Borg, F., Roach, A. G.: Effects of mianserin on noradrenaline uptake, cardiac presynaptic and vascular post-synaptic α-adrenoceptors in rats. Br. J. Pharmacol. 66, 132–133P (1979)
Clanachan, A. S., McGrath, J. C.: Effects of ketamine on the peripheral autonomic nervous system of the rat. Br. J. Pharmacol. 58, 247–252 (1976)
Docherty, J. R., McGrath, J. C.: Sympathomimetic effects of pancuronium bromide on the cardiovascular system of the pithed rat. Br. J. Pharmacol. 64, 589–599 (1978)
Docherty, J. R., McGrath, J. C.: An analysis of some factors influencing α-adrenoceptor feed-back at the sympathetic junction in the rat heart. Br. J. Pharmacol. 66, 55–63 (1979a)
Docherty, J. R., McGrath, J. C.: Inhibition of sympathetic transmission in rat heart by clonidine: the roles of stimulation frequency, endogenous feedback and noradrenaline re-uptake. Naunyn-Schmiedeberg's Arch. Pharmacol. 309, 225–233 (1979b)
Docherty, J. R., McGrath, J. C.: The factors influencing the time course of drug action at α-adrenoceptors: an investigation of the effects of clonidine in the pithed rat. Br. J. Pharmacol. 68, 225–234 (1980a)
Docherty, J. R., McGrath, J. C.: Further aspects of the autonomic side-effects of pancuronium bromide and a comparison with its mono-quaternary analogue Org NC 45. Br. J. Pharmacol. (in press, 1980b)
Docherty, J. R., MacDonald, A., McGrath, J. C.: Further subclassification of α-adrenoceptors in the cardiovascular system, vas deferens and anococcygeus of the rat. Br. J. Pharmacol. 67, 421–422P (1979)
Drew, G. M., Whiting, S. B.: Evidence for two distinct types of postsynaptic α-adrenoceptor in vascular smooth muscle. Br. J. Pharmacol. 67, 207–215 (1979)
Fludder, J. M., Leonard, B. E.: Chronic effects of mianserin on noradrenaline metabolism in the rat brain: evidence for a presynaptic α-adrenolytic action in vivo. Psychopharmacology 64, 329–332 (1979)
Gillespie, J. S.: Extraneuronal uptake of catecholamines in smooth muscle and connective tissues. In: The mechanism of neuronal and extraneuronal transport of catecholamines (D. M. Paton, ed.), pp. 325–354. New York: Raven Press 1976
Gillespie, J. S.: Effects on the autonomic and on the central nervous system. A. Presynaptic receptors in the autonomic nervous system. In: Handbook of experimental pharmacology, Vol. 54, Section II, pp. 169–205. Berlin, Heidelberg, New York: Springer 1980
Gillespie, J. S., McGrath, J. C.: The effect of pithing and of nerve stimulation on the depletion of noradrenaline by reserpine in the rat anococcygeus muscle and vas deferens. Br. J. Pharmacol. 52, 585–590 (1974)
Gillespie, J. S., MacLaren, A., Pollock, D.: A method of stimuiating different segments of the autonomic outflow from the spinal column to various organs in the pithed cat and rat. Br. J. Pharmacol. 40, 257–267 (1970)
Goodlet, I., Mireylees, S. E., Sugrue, M. F.: Effects of mianserin, a new antidepressant, on the in vitro and in vivo uptake of monoamines. Br. J. Pharmacol. 61, 307–313 (1977)
Lands, A. M., Arnold, A., McAuliff, J. P., Luduena, F. P., Brown, T. G., Jr.: Differentiation of receptor systems activated by sympathomimetic amines. Nature (Lond.) 214, 597–598 (1967)
Langer, S. Z.: The release of catecholamines from adrenergic neurons. A. Mechanism and regulation of nerve stimulation. In: Presynaptic adrenoceptors and regulation of release (D. M. Paton, ed.), pp. 59–86. Oxford: Pergamon Press 1979
Luchelli-Fortis, M. A., Langer, S. Z.: Reserpine-induced depletion of the norepinephrine stores: Is it a reliable criterion for the classification of the mechanism of action of sympathomimetic amines? J. Pharmacol. Exp. Ther. 188, 640–653 (1974)
McGrath, J. C.: Adrenergic and ‘non-adrenergic’ components in the contractile response of the vas deferens to a single indirect stimulus. J. Physiol. (Lond.) 283, 23–39 (1978)
Maxwell, R. A., Ferris, R. M., Burscu, J. E.: Structural requirements for inhibition of noradrenaline uptake by phenethylamine derivatives, desipramine, cocaine and other compounds. In: The mechanism of neuronal and extraneuronal transport of catecholamines (D. M. Paton, ed), pp. 95–154. New York: Raven Press 1976
Raiteri, M., Del Carmine, R., Cervoni, A. M., Levi, G.: Differential binding of antidepressants to noradrenaline and serotonin transport sites in central nerve endings. Eur. J. Pharmacol. 57, 407–416 (1979)
Robson, R. D., Antonaccio, M. J., Saelens, J. K., Liebman, J.: Antagonism by mianserin and classical α-adrenoceptor blocking drugs of some cardiovascular and behavioural effects of clonidine. Eur. J. Pharmacol. 47, 431–442 (1978)
Trendelenburg, U.: Classification of sympathomimetic amines. Chapter 10. In: Handbook of experimental pharmacology, Vol. XXIII, Catecholamines (H. Blaschko and E. Muscholl, eds), pp. 336–362. Berlin, Heidelberg, New York: Springer 1972
Trendelenburg, U.: The extraneuronal uptake and metabolism of catecholamines in the heart. In: The mechanism of neuronal and extraneuronal transport of catecholamines (D. M. Paton, ed), pp. 259–280. New York: Raven Press 1976
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Docherty, J.R., McGrath, J.C. An examination of factors influencing adrenergic transmission in the pithed rat, with special reference to noradrenaline uptake mechanisms and post-junctional α-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 313, 101–111 (1980). https://doi.org/10.1007/BF00498564
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DOI: https://doi.org/10.1007/BF00498564