Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension.

Autor:	Wainford RD; 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., Carmichael CY; 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.)., Pascale CL; 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.)., Kuwabara JT; 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.).
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2015 Jan; Vol. 65 (1), pp. 178-86. Date of Electronic Publication: 2014 Oct 13.
DOI:	10.1161/HYPERTENSIONAHA.114.04463
Abstrakt:	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. (© 2014 American Heart Association, Inc.)
Databáze:	MEDLINE
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