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Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension.
Hypertension 2015; 65(1):178-86H

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+Show Affiliations

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.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.).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.).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.).

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25312437

Citation

Wainford, Richard D., et al. "Gαi2-protein-mediated Signal Transduction: Central Nervous System Molecular Mechanism Countering the Development of Sodium-dependent Hypertension." Hypertension (Dallas, Tex. : 1979), vol. 65, no. 1, 2015, pp. 178-86.
Wainford RD, Carmichael CY, Pascale CL, et al. Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension. 2015;65(1):178-86.
Wainford, R. D., Carmichael, C. Y., Pascale, C. L., & Kuwabara, J. T. (2015). Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension (Dallas, Tex. : 1979), 65(1), pp. 178-86. doi:10.1161/HYPERTENSIONAHA.114.04463.
Wainford RD, et al. Gαi2-protein-mediated Signal Transduction: Central Nervous System Molecular Mechanism Countering the Development of Sodium-dependent Hypertension. Hypertension. 2015;65(1):178-86. PubMed PMID: 25312437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. AU - Wainford,Richard D, AU - Carmichael,Casey Y, AU - Pascale,Crissey L, AU - Kuwabara,Jill T, Y1 - 2014/10/13/ PY - 2014/10/15/entrez PY - 2014/10/15/pubmed PY - 2015/2/26/medline KW - blood pressure regulation KW - central G-protein–coupled receptors KW - renal sympathetic nerves KW - salt-sensitive hypertension KW - sympathetic nervous system SP - 178 EP - 86 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 65 IS - 1 N2 - 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. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/25312437/Gαi2_protein_mediated_signal_transduction:_central_nervous_system_molecular_mechanism_countering_the_development_of_sodium_dependent_hypertension_ L2 - http://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.114.04463?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -