Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart

    Authors

    C. Baker; D. G. Taylor; K. Osuala; A. Natarajan; P. J. Molnar; J. Hickman; S. Alam; B. Moscato; D. Weinshenker;S. N. Ebert

    Comments

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    Abbreviated Journal Title

    Biochem. Biophys. Res. Commun.

    Keywords

    Adrenergic regulation; Arrhythmia; Cardiac development; Cardiac gap; junctions; Conduction velocity; PHENYLETHANOLAMINE N-METHYLTRANSFERASE; CARDIAC CONDUCTION; GAP-JUNCTIONS; RAT-HEART; CATECHOLAMINES; CONNEXIN43; EXPRESSION; SYSTEM; GENE; MICE; Biochemistry & Molecular Biology; Biophysics

    Abstract

    To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine beta-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh(-/-)) relative to adrenergic-competent (Dbh(+/+) and Dbh(+/-)) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8 x 8,200 mu m apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4 +/- 6.4 vs. 15.4 +/- 1.7 ms, respectively, p < 0.05). To determine if the absence of adrenergic hormones affected heart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the beta-adrenergic receptor agonist, isoproterenol (0.5 mu M). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (p < 0.05) 225% increase in the arrhythmic index (AI) was observed only in adrenergic-deficient hearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development. (C) 2012 Elsevier Inc. All rights reserved.

    Journal Title

    Biochemical and Biophysical Research Communications

    Volume

    423

    Issue/Number

    3

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    536

    Last Page

    541

    WOS Identifier

    WOS:000306624900017

    ISSN

    0006-291X

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