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

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. Gα s activates adenylyl cyclases, which drive cyclic adenosine monophosphate (cAMP)-depe...

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Published in:The Journal of pharmacology and experimental therapeutics 2016-02, Vol.356 (2), p.424-433
Main Authors: Tallapragada, Vikram J, Hildreth, Cara M, Burke, Peter G R, Raley, Darryl A, Hassan, Sarah F, McMullan, Simon, Goodchild, Ann K
Format: Article
Language:English
Subjects:
Animals
Baroreflex - drug effects
Baroreflex - physiology
Blood Pressure - drug effects
Blood Pressure - physiology
Cyclic AMP - analogs & derivatives
Cyclic AMP - pharmacology
Heart Rate - drug effects
Heart Rate - physiology
Male
Medulla Oblongata - drug effects
Medulla Oblongata - physiology
Rats
Rats, Sprague-Dawley
Signal Transduction - drug effects
Signal Transduction - physiology
Sympathetic Nervous System - drug effects
Sympathetic Nervous System - physiology
Vagus Nerve - drug effects
Vagus Nerve - physiology
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Summary: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. Gα s 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 Gα s-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.
ISSN:1521-0103
1521-0103
DOI:10.1124/jpet.115.227488