RT Journal Article
SR Electronic
T1 TONICALLY ACTIVE cAMP DEPENDENT SIGNALLING IN THE VENTROLATERAL MEDULLA REGULATES SYMPATHETIC AND CARDIAC VAGAL OUTFLOWS
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.227488
DO 10.1124/jpet.115.227488
A1 Vikram J Tallapragada
A1 Cara M Hildreth
A1 Peter G.R. Burke
A1 Darryl A Raley (deceased)
A1 Sarah F Hassan
A1 Simon McMullan
A1 Ann K Goodchild
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/11/17/jpet.115.227488.abstract
AB 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 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-anaesthetized 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 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 reflexes. Sp-cAMPs also increased cardiac vagal drive and facilitated cardiac baroreflex sensitivity. Blockade of PKA, using Rp-cAMPs or H-89 in RVLM increased sSNA, AP and HR and increased HR when cardiac vagal preganglionic neurons were targeted. BFA, which inhibits EPAC, and ZD7288, which inhibits HCN channels, alone each 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.