Brain Gαi2-subunit proteins and the prevention of salt sensitive hypertension

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 G alpha-subunit proteins in these critically important physiological regulatory responses required for long-term blood pressure regulation. We have determined that brain G alpha i(2)-proteins mediate natriuretic and sympathoinhibitory responses produced by acute pharmacological (exogenous central nociceptin/orphanin FQ receptor (NOP) and (alpha(2)-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 upregulation of hypothalamic paraventricular nucleus (PVN) G alpha i(2)-proteins. Further, we established that PVN G alpha i(2) 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 G alpha i(2) 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, G alpha i(2) 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.