β-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth

Gwenaëlle L. Clarke, Aritra Bhattacherjee, Sarah E. Tague, Wohaib Hasan, Peter G. Smith

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β1-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β2-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β1-adrenoceptors. Immunohistochemistry revealed β1-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β1-autoreceptors that negatively regulate axon out-growth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.

    Original languageEnglish (US)
    Pages (from-to)12446-12454
    Number of pages9
    JournalJournal of Neuroscience
    Volume30
    Issue number37
    DOIs
    StatePublished - Sep 15 2010

    Fingerprint

    Autoreceptors
    Adrenergic Receptors
    Axons
    Propranolol
    Growth
    Norepinephrine
    Metoprolol
    Tyramine
    Adrenergic Antagonists
    Dobutamine
    Isoproterenol
    Ligation
    Tyrosine
    Noise
    Coronary Vessels
    Arterial Pressure
    Heart Failure
    Cell Culture Techniques
    Immunohistochemistry
    Air

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Medicine(all)

    Cite this

    β-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth. / Clarke, Gwenaëlle L.; Bhattacherjee, Aritra; Tague, Sarah E.; Hasan, Wohaib; Smith, Peter G.

    In: Journal of Neuroscience, Vol. 30, No. 37, 15.09.2010, p. 12446-12454.

    Research output: Contribution to journalArticle

    Clarke, Gwenaëlle L. ; Bhattacherjee, Aritra ; Tague, Sarah E. ; Hasan, Wohaib ; Smith, Peter G. / β-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 37. pp. 12446-12454.
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