Hypothalamic Paraventricular Nucleus Gαq Subunit Protein Pathways Mediate Vasopressin Dysregulation and Fluid Retention in Salt-Sensitive Rats

Central G alpha z and G alpha q protein-gated pathways play a pivotal role in modulating (inhibiting vs. stimulating, respectively) vasopressin release and urine output; these studies examined the role of brain G alpha z/G alpha q proteins in the regulation of vasopressin secretion during high-salt challenge. We examined the effects of 21-d normal or high salt intake on plasma vasopressin levels, daily sodium and water balance, and brain G alpha z and G alpha q protein levels in male Sprague-Dawley (SD), Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. Additionally, the effect of central G alpha q protein down-regulation on these parameters and the diuretic response evoked by pharmacological [nociceptin/orphanin FQ; 5.5 nmol intracerebroventricularly (icv)] and physiological stimuli (isotonic-saline volume expansion, 5% bodyweight, iv) was examined. After 21 d of high salt intake, DSS, but not SD or DSR rats, exhibited vasopressin dysregulation, as evidenced by elevated plasma vasopressin levels (P < 0.05), marked positive water (and sodium) balance (P < 0.05), and an impaired diuretic response to pharmacological and physiological stimuli (P < 0.05). Chronic high salt intake (21 d) evoked down-regulation of G alpha q (P < 0.05), but not G alpha z, proteins in the hypothalamic paraventricular nucleus of SD and DSR, but not DSS rats. In salt-challenged (21 d) DSS rats, acute oligodeoxynucleotide-mediated down-regulation of central G alpha q proteins returned plasma vasopressin to control levels (P < 0.05), decreased salt-induced water retention (P < 0.05), and restored the profound diuretic responses to pharmacological and physiological stimuli (P < 0.05). Therefore, the down-regulation of PVN G alpha q proteins plays a critical counter-regulatory role in preventing vasopressin hypersecretion in salt-resistant phenotypes and may represent a new therapeutic target in pathophysiological states featuring vasopressin dysregulation. (Endocrinology 151: 5403-5414, 2010)