title: Tonically Active cAMP-Dependent Signaling in the Ventrolateral Medulla Regulates Sympathetic and Cardiac Vagal Outflows.
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. 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.
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Vikram J
authors.initials: VJ
authors.lastname: Tallapragada
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Hildreth
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Peter G R
authors.initials: PG
authors.lastname: Burke
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Raley
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Hassan
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: McMullan
authors.affiliation: Dept Biomedical Sciences, Faculty of Medicine, Macquarie University, Sydney, NSW, Australia ann.goodchild@mq.edu.au.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Goodchild
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D000242:Cyclic AMP