Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus

Authors

  • Gabriela Cristina Brailoiu,

    1. Department of Pharmaceutical Sciences, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, Pennsylvania, USA
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  • Elena Deliu,

    1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
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  • Joseph E. Rabinowitz,

    1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
    2. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
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  • Douglas G. Tilley,

    1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
    2. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
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  • Walter J. Koch,

    1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
    2. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
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  • Eugen Brailoiu

    Corresponding author
    1. Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
    2. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
    • Address correspondence and reprint requests to Eugen Brailoiu, Center for Translational Medicine, Temple University School of Medicine, 3500 N. Broad Street, Room 951, Philadelphia, PA 19140, USA. E-mail: ebrailou@temple.edu

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Abstract

Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of U-II and its receptor at this level. We report here that U-II produces an increase in cytosolic Ca2+ concentration in retrogradely labeled cardiac vagal neurons of nucleus ambiguus via two pathways: (i) Ca2+ release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptor; and (ii) Ca2+ influx through P/Q-type Ca2+ channels. In addition, U-II depolarizes cultured cardiac parasympathetic neurons. Microinjection of increasing concentrations of U-II into nucleus ambiguus elicits dose-dependent bradycardia in conscious rats, indicating the in vivo activation of the cholinergic pathway controlling the heart rate. Both the in vitro and in vivo effects were abolished by the urotensin receptor antagonist, urantide. Our findings suggest that, in addition, to the previously reported increase in sympathetic outflow, U-II activates cardiac vagal neurons of nucleus ambiguus, which may contribute to cardioprotection.

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Our study characterizes the effects of urotensin II (U-II) on cardiac-projecting nucleus ambiguus neurons. U-II depolarizes these neurons, promotes Ca2+ entry via P/Q-type Ca2+ channels and Ca2+ release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors. U-II microinjection into the nucleus ambiguus elicits bradycardia in conscious rats. Thus, U-II increases cardiac vagal tone, potentially promoting cardioprotection, as previously reported.

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