Brain Gαi 2 -subunit proteins and the prevention of salt sensitive hypertension

Abstract

To counter the development of salt-sensitive hypertension, multiple brain G-protein-coupled receptor (GPCR) systems are activated to facilitate sympathoinhibition, sodium homeostasis, and normotension. Currently there is a paucity of knowledge regarding the role of down-stream GPCR-activated Gα-subunit proteins in these critically important physiological regulatory responses required for long-term blood pressure regulation. We have determined that brain Gαi2-proteins mediate natriuretic and sympathoinhibitory responses produced by acute pharmacological (exogenous central nociceptin/orphanin FQ receptor (NOP) and α2-adrenoceptor activation) and physiological challenges to sodium homeostasis (intravenous volume expansion and 1 M sodium load) in conscious Sprague-Dawley rats. We have demonstrated that in salt-resistant rat phenotypes, high dietary salt intake evokes site-specific up-regulation of hypothalamic paraventricular nucleus (PVN) Gαi2-proteins. Further, we established that PVN Gαi2 protein up-regulation prevents the development of renal nerve-dependent sympathetically mediated salt-sensitive hypertension in Sprague-Dawley and Dahl salt-resistant rats. Additionally, failure to up-regulate PVN Gαi2 proteins during high salt-intake contributes to the pathophysiology of Dahl salt-sensitive (DSS) hypertension. Collectively, our data demonstrate that brain, and likely PVN specific, Gαi2 protein pathways represent a central molecular pathway mediating sympathoinhibitory renal-nerve dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Further, impairment of this endogenous "anti-hypertensive" mechanism contributes to the pathophysiology of salt-sensitive hypertension.

Keywords: blood pressure regulation; central G-protein coupled receptors; central Gαi2 proteins; renal sympathetic nerves; salt-sensitive hypertension; sodium homeostasis; sympathetic nervous system.

Figure 1

Schematic representation of the major Gα protein signal transduction pathways activated following ligand binding at a G-protein coupled receptor.

Figure 2

Schematic representation of the functional selectivity of G-protein coupled receptor activated Gα protein signal transduction pathways in mediating the physiological responses evoked by central exogenous administration of N/OFQ and Guanbenz or the physiological stimuli of an iv volume expansion or sodium load. AVP, vasopressin; NE, Norepinephrine; NOP, nociceptin/orphanin FQ receptor; RSNA, renal sympathetic nerve activity.

Figure 3

Schematic representation of the differential impact of elevated dietary sodium intake on PVN Gαi₂ protein expression and the consequences of this on central sympathetic outflow, sodium homeostasis, and blood pressure in salt-resistant vs. salt-sensitive phenotypes. MAP, mean arterial pressure; NE, Norepinephrine; PVN, paraventricular nucleus.