Xiao C Li
University of Mississippi Medical Center USA
Title: Inhibition of NHE3 in the proximal tubule of the kidney by an orally absorbable NHE3 inhibitor attenuates angiotensin II-induced hypertension in mice
Biography
Biography: Xiao C Li
Abstract
We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global (Nhe3-/-) and Nhe3-/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tgNhe3-/-), suggesting a significant role of NHE3 in the development of ANG II-dependent hypertension. The present study tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubule of the kidney attenuates ANG II-dependent hypertension induced by a slow pressor dose of ANG II supplemented with 2% high salt diet. 9 groups (n=6-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via mini pump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116±2 mmHg to 140±2 mmHg (p<0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147±4 mmHg (p<0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125±4 mmHg in ANG II-infused mice (p<0.01), and to 134±6 mmHg in ANG II-infused mice supplemented with 2% NaCl (p<0.01), respectively. Further treatment with AVE0657 and losartan, an AT1 receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115±5 mmHg, p<0.01). AVE0657 significantly increased 24 h urinary Na+ excretion (p<0.01) but had no effect on 24 h fecal Na+ excretion in control or ANG II-infused mice. These results provide preclinical evidence that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to treat ANG II-dependent hypertension by inhibiting NHE3 and Na+ reabsorption in the proximal tubule of the kidney.