Attenuated Aortic Vasodilation and Sympathetic Prejunctional Facilitation in Epinephrine-Deficient Mice: Selective Impairment of beta(2)-Adrenoceptor Responses

    Authors

    M. Moreira-Rodrigues; A. L. Graca; M. Ferreira; J. Afonso; P. Serrao; M. Morato; F. Ferreirinha; P. Correia-de-Sa; S. N. Ebert;D. Moura

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    Abbreviated Journal Title

    J. Pharmacol. Exp. Ther.

    Keywords

    PHENYLETHANOLAMINE N-METHYLTRANSFERASE; BETA-ADRENOCEPTORS; POSTNATAL-DEVELOPMENT; SAPHENOUS-VEIN; RECEPTOR; MOUSE; RAT; INHIBITION; TRANSMISSION; ACTIVATION; Pharmacology & Pharmacy

    Abstract

    It has been suggested that there is a link between epinephrine synthesis and the development of beta(2)-adrenoceptor-mediated effects, but it remains to be determined whether this development is triggered by epinephrine. The aim of this study was to characterize beta-adrenoceptor-mediated relaxation and facilitation of norepinephrine release in the aorta of phenylethanolamine-N-methyltransferase-knockout (Pnmt-KO) mice. Catecholamines were quantified by reverse-phase high-performance liquid chromatography-electrochemical detection. Aortic rings were mounted in a myograph to determine concentration-response curves to selective beta(1)- or beta(2)-adrenoceptor agonists in the absence or presence of selective beta(1)- or beta(2)-adrenoceptor antagonists. Aortic rings were also preincubated with [H-3] norepinephrine to measure tritium overflow elicited by electrical stimulation in the presence of increasing concentrations of nonselective beta- or selective beta(2)-adrenoceptor agonists. beta(2)-Adrenoceptor protein density was evaluated by Western blotting and beta(2)-adrenoceptor localization by immunohistochemistry. Epinephrine is absent in Pnmt-KO mice. The potency and the maximal effect of the beta(2)-adrenoceptor agonist terbutaline were lower in Pnmt-KO than in wild-type (WT) mice. The selective beta(2)-adrenoceptor antagonist ICI 118,551 [(+/-)-erythro-(S*, S*)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride] antagonized the relaxation caused by terbutaline in WT but not in Pnmt-KO mice. Isoproterenol and terbutaline induced concentration-dependent increases in tritium overflow in WT mice only. beta(2)-Adrenoceptor protein density was decreased in membrane aorta homogenates of Pnmt-KO mice, and this finding was supported by immunofluorescence confocal microscopy. In conclusion, epinephrine is crucial for beta(2)-adrenoceptor-mediated vasodilation and facilitation of norepinephrine release. In the absence of epinephrine, beta(2)-adrenoceptor protein density was decreased in aorta cell membranes, thus potentially hindering its functional activity.

    Journal Title

    Journal of Pharmacology and Experimental Therapeutics

    Volume

    351

    Issue/Number

    2

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    243

    Last Page

    249

    WOS Identifier

    WOS:000341944900002

    ISSN

    0022-3565

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