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Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon

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Abstract

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI.

DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular β-adrenoceptors) and clonidine (acting on neuronal α2-adrenoceptors) and supersensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.

We conclude that in the guinea-pig colon: 1) α- and β-adrenoceptors are under tonic neuronal control, as indicated by the sensitivity changes to α- and β-adrenoceptor agonists after chronic DMI treatment; 2) exogenous NA reaching neuronal, but not muscular adrenoceptors, is affected by neuronal uptake mechanisms; 3) NA released by adrenergic terminals undergoes neuronal uptake and is controlled by α2-autoreceptors.

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  1. Manuela Marcoli

    Present address: Istituto di Farmacologia, Università degli Studi di Genova, I-16100, Genova, Italy

Authors and Affiliations

  1. Department of Internal Medicine and Therapeutics, II Faculty of Medicine, University of Pavia, Viale Luigi Borri 57, I-21100, Varese VA, Italy

    Franca Marino, Manuela Marcoli, Fabrizio De Ponti, Marco Cosentino, Sergio Lecchini & Gian Mario Frigo

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  1. Franca Marino
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Correspondence to: G. M. Frigo at the above address

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Marino, F., Marcoli, M., De Ponti, F. et al. Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon. Naunyn-Schmiedeberg's Arch Pharmacol 350, 499–506 (1994). https://doi.org/10.1007/BF00173019

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