Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs.

Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol. 2016 Feb 17;:ajprenal.00473.2015 Authors: Ramseyer VD, Ortiz PA, Carretero OA, Garvin JL Abstract In thick ascending limbs (THALs) NO decreases NaCl reabsorption via cGMP-mediated inhibition of Na/K/2Cl cotransporter (NKCC2). In angiotensin (Ang II)-induced hypertension, endothelin-1 (ET-1)-induced NO production by THALs is impaired. However, whether this alters NO's natriuretic effects and the mechanisms involved are unknown. In other cell types, Ang II augments phosphodiesterase 5 (PDE5)-mediated cGMP degradation. We hypothesized that NO-mediated inhibition of NKCC2 activity and stimulation of cGMP synthesis are blunted via PDE5 in Ang II-induced hypertension. Sprague Dawley rats were infused with vehicle or Ang II (200ng/kg/min) for 5 days. ET-1 reduced NKCC2 activity by 38±13% (p<0.05) in THALs from vehicle-treated rats but not from Ang II-hypertensive rats (Δ:-9±13 %). A NO donor yielded similar results as ET-1. In contrast, dibutyryl-cGMP significantly decreased NKCC2 activity in both vehicle-treated and Ang II-hypertensive rats (control: Δ -44±15 % vs Ang II: Δ -41±10%). NO increased cGMP by 2.08±0.36 fmol/µg protein in THALs from vehicle-treated rats but only 1.06±0.25 fmol/µg protein in Ang II-hypertensive rats (p<0.04). Vardenafil (25 nM), a PDE5 inhibitor, restored NO's a...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research