Effects of the selective chymase inhibitor, TEI-F00806, on intrarenal renin-angiotensin system in salt-treated angiotensin I-infused hypertensive mice

Abstract

We have previously shown that chymase play an important role in the regulation of local tissue renin-angiotensin system. Here, studies were performed to examine the effect of TEI-F00806, the selective chymase inhibitor, on angiotensin I (Ang I)-induced hypertension and intrarenal angiotensin II (Ang II) production in salt-treated mice. Twelve-week-old wt male mice were given high salt diet (4% NaCl) + saline (0.9% NaCl), and divided into three groups; 1) sham, 2) Ang I (1 µg/kg/ min, s.c.) or 3) Ang I + TEI-F00806 (100 mg/kg/day, p.o.)(n= 8-10 for each). Systolic blood pressure (SBP) was measured every week using a tail-cuff method. Kidney Ang II contents were measured by radioimmunoassay. Chronic infusion of Ang I developed hypertension and augmented intrarenal chymase gene expression, angiotensinogen protein levels and Ang II contents in salt-treated mice (p < 0.05, p < 0.001, p < 0.01 respectively). Treatment with TEI-F00806 attenuated the development of hypertension (p < 0.001) and decreased Ang II contents in the kidney (p < 0.05), which were associated with reductions in renal cortical angiotensinogen protein levels and chymase mRNA expression (p < 0.0001, p < 0.05 respectively). These data indicate that a chymase inhibitor decreases intrarenal renin-angiotensin activity and thereby blunted the salt-dependent blood pressure elevation.