title: Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension.
abstract: Excess dietary salt intake is an established cause of hypertension. At present, our understanding of the neuropathophysiology of salt-sensitive hypertension is limited by a lack of identification of the central nervous system mechanisms that modulate sympathetic outflow and blood pressure in response to dietary salt intake. We hypothesized that impairment of brain Gαi2-protein-gated signal transduction pathways would result in increased sympathetically mediated renal sodium retention, thus promoting the development of salt-sensitive hypertension. To test this hypothesis, naive or renal denervated Dahl salt-resistant and Dahl salt-sensitive (DSS) rats were assigned to receive a continuous intracerebroventricular control scrambled or a targeted Gαi2-oligodeoxynucleotide infusion, and naive Brown Norway and 8-congenic DSS rats were fed a 21-day normal or high-salt diet. High salt intake did not alter blood pressure, suppressed plasma norepinephrine, and evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi2-protein levels in naive Brown Norway, Dahl salt-resistant, and scrambled oligodeoxynucleotide-infused Dahl salt-resistant but not DSS rats. In Dahl salt-resistant rats, Gαi2 downregulation evoked rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation. In DSS rats, Gαi2 downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Congenic-8 DSS rats exhibited sodium-evoked paraventricular nucleus-specific Gαi2-protein upregulation and attenuated hypertension, sodium retention, and global sympathoexcitation compared with DSS rats. These data demonstrate that paraventricular nucleus Gαi2-protein-gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Impairment of this mechanism contributes to the development of salt-sensitive hypertension.
authors.affiliation: From the the Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (R.D.W., C.Y.C., J.T.K.); and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans (R.D.W., C.L.P.). rwainf@bu.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wainford
authors.affiliation: From the the Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (R.D.W., C.Y.C., J.T.K.); and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans (R.D.W., C.L.P.).
authors.forename: Casey Y
authors.initials: CY
authors.lastname: Carmichael
authors.affiliation: From the the Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (R.D.W., C.Y.C., J.T.K.); and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans (R.D.W., C.L.P.).
authors.forename: Crissey L
authors.initials: CL
authors.lastname: Pascale
authors.affiliation: From the the Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (R.D.W., C.Y.C., J.T.K.); and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans (R.D.W., C.L.P.).
authors.forename: Jill T
authors.initials: JT
authors.lastname: Kuwabara
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002490:Central Nervous System / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000096:biosynthesis*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D015151:Immunoblotting; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction; D012982:Sodium, Dietary / Q000633:toxicity
chemical_list: D012982:Sodium, Dietary; D051960:GTP-Binding Protein alpha Subunit, Gi2
keywords: blood pressure regulation; central G-protein–coupled receptors; renal sympathetic nerves; salt-sensitive hypertension; sympathetic nervous system