Hypothalamic paraventricular nucleus G alpha q subunit protein pathways mediate vasopressin dysregulation and fluid retention in salt-sensitive rats.
Central Gαz and Gαq 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 Gαz/Gαq 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 Gαz and Gαq protein levels in male Sprague-Dawley (SD), Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. Additionally, the effect of central Gαq 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 Gαq (P < 0.05), but not Gαz, 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 Gαq 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 Gαq 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.
Wainford
Richard D
RD
Department of Pharmacology, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, Louisiana 70112, USA. rwainf@lsuhsc.edu
Kapusta
Daniel R
DR
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001834:Body Water / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D008297:Male; D018847:Opioid Peptides / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism*; D000097629:Nociceptin
D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D018847:Opioid Peptides; D017673:Sodium Chloride, Dietary; D014667:Vasopressins; D000097629:Nociceptin