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Brain Gαi2-subunit protein-gated pathways are required to mediate the centrally evoked sympathoinhibitory mechanisms activated to maintain sodium homeostasis

Wainford, Richard D.a,b; Pascale, Crissey L.a; Kuwabara, Jill T.b

doi: 10.1097/HJH.0b013e32835ebd54
ORIGINAL PAPERS: Sympathetic activity

Objective: We have previously demonstrated a role of GPCR-activated brain Gαi2-subunit protein-gated pathways in the natriuretic responses evoked by exogenous central α2-adrenoceptor activation and acute intravenous (i.v.) volume expansion in vivo. Our objective was to examine the role of brain Gαi2 proteins in the integrated neural-humoral responses evoked by i.v. isovolumetric sodium loading, which does not alter mean arterial blood pressure or total blood volume, to maintain sodium homeostasis in conscious Sprague-Dawley rats.

Methods: Intact or chronic bilateral renal denervated (RDNX) rats were pretreated intracerebroventricularly (i.c.v.) with a scrambled or Gαi2 oligodeoxynucleotide to selectively downregulate brain Gαi2 proteins. On the day of study, an i.v. isovolumetric sodium load (1 mol/l NaCl) was administered.

Results: In naive and scrambled oligodeoxynucleotide groups, i.v. sodium loading evoked profound natriuresis, suppression of plasma renin activity (PRA) and global sympathoinhibition. Prior downregulation of brain Gαi2 proteins significantly attenuated the natriuretic response [peak ΔUNaV (μeq/μl); scrambled 22 ± 2 vs. Gαi2 13 ± 2, P < 0.05] and abolished the sympathoinhibitory response [peak Δplasma norepinephrine (% control); SCR −72 ± 8 vs. Gαi2 −7 ± 5, P < 0.05] without attenuating PRA suppression to sodium loading. In RDNX rats, Gαi2 oligodeoxynucleotide pretreatment failed to attenuate the natriuretic response [peak ΔUNaV (μeq/μl); RDNX and scrambled 19 ± 3 vs. RDNX and Gαi2 20 ± 2] and only partially prevented the sympathoinhibitory response to i.v. sodium loading.

Conclusion: These studies reveal a brain Gαi2-subunit protein-mediated (renin–angiotensin system-independent) sympathoinhibitory pathway that has a critical role in the central neural mechanisms activated to maintain fluid and electrolyte homeostasis.

aDepartment of Pharmacology and Experimental Therapeutics and the Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana

bThe Department of Pharmacology & Experimental Therapeutics and The Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA

Correspondence to Richard D. Wainford, Department of Pharmacology & Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA. Tel: +1 617 414 2648; fax: +1 617 638 4329; e-mail:

Abbreviations: CNS, central nervous system; EBV, estimated blood volume; EPV, estimated plasma volume; GPCR, G-protein coupled receptor; Hct, Hematocrit; HR, heart rate; i.c.v., intracerebroventricular; MAP, mean arterial pressure; PRA, plasma renin activity; PVN, paraventricular nucleus; RDNX, bilateral renal denervation; RSNA, renal sympathetic nerve activity; UNaV, urinary sodium excretion; V, urine volume; VLM, ventrolateral medulla

Received 30 March, 2012

Revised 12 December, 2012

Accepted 8 January, 2013

© 2013 Lippincott Williams & Wilkins, Inc.