The Natriuretic and Diuretic Response to Uroguanylin is Blunted in Dahl‐Salt Sensitive Rats

Abstract

Uroguanylin (UGN) is a 17 aminoacids long peptide with diuretic and natriuretic activity. UGN, an intestinal natriuretic peptide, is delivered to the kidney as an unprocessed propeptide, prouroguanylin (pro‐UGN). Circulating pro‐UGN is processed to its active natriuretic form exclusively within the renal tubules. The circulating levels of pro‐UGN and the urinary levels of UGN are increased during sodium overload and this natriuretic peptide and the kidney response to UGN is increased in rats maintained in a high salt intake. We hypothesized that the diuretic and natriuretic response to UGN are altered in Dahl‐salt sensitive rats (DS) as compared to Wistar (WR) rats. Dahl‐salt sensitive (DS) rats (n=5/group) received water with 1% NaCl during 15 days and the tail systolic blood pressure (mmHg) increased from 108.0±2.0 to 145.9±2.6 while no remarkable changes were observed in Wistar rats. After the end of this period, rats were anesthetized and prepared for classical renal clearance and hemodynamics studies. After a 1‐hour control period, UGN was intravenously infused at 100nmoles/kg/min rate during 1‐hour period and heart rate (HR), mean arterial pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), renal blood flow (RBF), urine output (V′), UNaV and fractional sodium excretion (FENa+) were evaluated during infusion and for an additional 1‐hour post‐infusion period. No significant changes were observed for HR, MAP, RVR or RBF in any group or period during the whole experimental period. UGN did not change GFR (ml/g/min) in WR rats but increased it from 1.7±0.8 to 4.4±1.1 in DS rats. In addition, UGN infusion induced a significant diuresis that was stable during the infusion and post‐infusion period. The urinary output (μL/g of kidney/min) increased from 6.7±1.1 to 21.6±5.4 (p<0.001) during the infusion with UGN in WR and from 5.7±2.6 to 11.5±3.6 in DS. Strikingly, the basal levels of UnaV (μEq/g of kidney/min) in DS are significantly lower than the levels observed for WR (0.04±0.01‐DS vs. 0.23±0.07‐p<0.001). The infusion of UGN increases UNaV from 0.23±0.07 to 0.48±0.01 (p<0.01) in WR and from 0.04±0.01 to 0.27±0.08 (P<0.001). Similarly, the basal FENa+ is remarkably lower in DS when compared to WR. DS rats excrete 10 times less sodium than WR. The infusion of UGN does not increase FENa+ (%) in DS but induced a 60% increase in in WR from 1.5±0.12 to 2.5±0.16 at the end of the infusion period. The diuretic and natriuretic effects of UGN are blunted in DS rats. The defect of this counter regulatory mechanism may have a role in the genesis and maintenance of hypertension in this strain of rats.Support or Funding InformationCNPq, FUNCAP and CAPES