Brain Gαz/Gαq subunit protein‐gated pathways participate in regulating AVP secretion and urine output during conditions in which water homeostasis is challenged

Abstract

Hypothesis Brain Gαz/Gαq protein pathways play a critical role in maintaining water homeostasis by regulating AVP release and urine output in vivo. Methods Sprague-Dawley rats were pre-treated intracerebroventricularly (i.c.v.) with an oligodeoxynucleotide (ODN) targeted towards a Gαz, Gαq, or a scrambled (SCR) sequence (24hrs, 25 μg; N=6/group). In volume overload studies, urine output (V) was measured for 90-min in instrumented rats subjected to an acute i.v. isotonic saline volume expansion (VE, 3%BW for 30-min). In volume deprivation (VD) studies, spontaneous urine output was measured before (control) and during water restriction for 6-hr, after which rats were sacrificed for trunk blood collection and plasma AVP measurement. Urine Output (V) VE Study Control (μl/min) Peak (μl/min) (30-min post-VE) Cumulative (ml) (120 min post-VE) SCR ODN 24.6±2.5 135.2±12.6* 8.67+/− 0.80 Gz ODN 18.1±2.6 76.5±8.7*τ 6.70+/− 0.40τ Gq ODN 26.6±5.2 136.6±10.7* 10.79 +/− 0.70τ VD Study Control (ml/3hr) V: 1–3 hrs Post-VD (ml) V: 3–6 hrs Post-VD (ml) Plasma [AVP] (pg/ml) SCR ODN 2.35±0.63 1.78±0.42 0.78±0.23* 11.3±0.6 Gz ODN 1.76±0.20 1.53±0.28 0.58±0.12* 8.7±0.8τ Gq ODN 2.56±0.41 2.02±0.60 2.59±0.60 5.1±0.5τ * P<0.05 vs. resp. control value; τ p<0.05 vs. group SCR value. Results Selective down-regulation of central Gα protein pathways significantly blunted (Gz ODN) or enhanced (Gq ODN) the diuretic response to acute VE. During water deprivation, down-regulation of brain Gαq proteins prevented the maximal increase in plasma AVP levels and water retention. Conclusions Brain Gαz/Gαq subunit protein-gated pathways play a physiological role in regulating AVP secretion and urine output during conditions in which water homeostasis is challenged. NIH DK4337, HL071212, P20RR018766 and AHA 0855293E to DRK