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

Abstract

What is the central question of this study? Can chymase inhibition prevent angiotensin I-induced hypertension through inhibiting the conversion of angiotensin I to angiotensin II in the kidney? What is the main finding and its importance? Treatment with TEI-F00806 decreased angiotensin II content of the kidney, renal cortical angiotensinogen protein levels and chymase mRNA expression, and attenuated the development of hypertension. The effects of the selective chymase inhibitor TEI-F00806 were examined on angiotensin I (AngI)-induced hypertension and intrarenal angiotensin II (AngII) production in salt-treated mice. Twelve-week-old C57BL male mice were given a high-salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) AngI (1μgkg-1 min-1 , s.c.) + vehicle, and (3) AngI + TEI-F00806 (100mgkg-1 day-1 , p.o.) (n=8-10 per group). Systolicblood pressurewas measured weekly using atail-cuffmethod. Kidney AngII content was measured by radioimmunoassay. Chronic infusion of AngI resulted in the development of hypertension (P<0.001), and augmented intrarenal chymase gene expression (P<0.05), angiotensinogen protein level (P<0.001) and AngII content (P<0.01) in salt-treated mice. Treatment with TEI-F00806 attenuated the development of hypertension (P<0.001) and decreased AngII content of the kidney (P<0.05), which was associated with reductions in renal cortical angiotensinogen protein levels (P<0.001) and chymase mRNA expression (P<0.05). These data suggest that a chymase inhibitor decreases intrarenal renin-angiotensin activity, thereby reducing salt-dependent hypertension.