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Research ArticleNeuropharmacology

Tonically Active cAMP-Dependent Signaling in the Ventrolateral Medulla Regulates Sympathetic and Cardiac Vagal Outflows

Vikram J. Tallapragada, Cara M. Hildreth, Peter G.R. Burke, Darryl A. Raley, Sarah F. Hassan, Simon McMullan and Ann K. Goodchild
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 424-433; DOI: https://doi.org/10.1124/jpet.115.227488
Vikram J. Tallapragada
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Cara M. Hildreth
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Peter G.R. Burke
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Darryl A. Raley
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Sarah F. Hassan
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Simon McMullan
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Ann K. Goodchild
Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
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Abstract

The ventrolateral medulla contains presympathetic and vagal preganglionic neurons that control vasomotor and cardiac vagal tone, respectively. G protein-coupled receptors influence the activity of these neurons. Gαs activates adenylyl cyclases, which drive cyclic adenosine monophosphate (cAMP)–dependent targets: protein kinase A (PKA), the exchange protein activated by cAMP (EPAC), and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels. The aim was to determine the cardiovascular effects of activating and inhibiting these targets at presympathetic and cardiac vagal preganglionic neurons. Urethane-anesthetized rats were instrumented to measure splanchnic sympathetic nerve activity (sSNA), arterial pressure (AP), heart rate (HR), as well as baroreceptor and somatosympathetic reflex function, or were spinally transected and instrumented to measure HR, AP, and cardiac baroreflex function. All drugs were injected bilaterally. In the rostral ventrolateral medulla (RVLM), Sp-cAMPs and 8-Br-cAMP, which activate PKA, as well as 8-pCPT, which activates EPAC, increased sSNA, AP, and HR. Sp-cAMPs also facilitated the reflexes tested. Sp-cAMPs also increased cardiac vagal drive and facilitated cardiac baroreflex sensitivity. Blockade of PKA, using Rp-cAMPs or H-89 in the RVLM, increased sSNA, AP, and HR and increased HR when cardiac vagal preganglionic neurons were targeted. Brefeldin A, which inhibits EPAC, and ZD7288, which inhibits HCN channels, each alone had no effect. Cumulative, sequential blockade of all three inhibitors resulted in sympathoinhibition. The major findings indicate that Gαs-linked receptors in the ventral medulla can be recruited to drive both sympathetic and parasympathetic outflows and that tonically active PKA-dependent signaling contributes to the maintenance of both sympathetic vasomotor and cardiac vagal tone.

Footnotes

    • Received July 20, 2015.
    • Accepted November 13, 2015.
  • This work was supported by the National Health and Medical Research Council [APP1028183, APP1030301], the Australian Research Council [DP120100920], and the Hillcrest Foundation [FR2013/1308, FR2014/0781]. Dr. Darryl Raley died before the completion of this study.

  • dx.doi.org/10.1124/jpet.115.227488.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
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Research ArticleNeuropharmacology

cAMP Signaling in the Ventrolateral Medulla

Vikram J. Tallapragada, Cara M. Hildreth, Peter G.R. Burke, Darryl A. Raley, Sarah F. Hassan, Simon McMullan and Ann K. Goodchild
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 424-433; DOI: https://doi.org/10.1124/jpet.115.227488

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Research ArticleNeuropharmacology

cAMP Signaling in the Ventrolateral Medulla

Vikram J. Tallapragada, Cara M. Hildreth, Peter G.R. Burke, Darryl A. Raley, Sarah F. Hassan, Simon McMullan and Ann K. Goodchild
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 424-433; DOI: https://doi.org/10.1124/jpet.115.227488
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