Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

Abstract

Devarajan S, Yahiro E, Uehara Y, Habe S, Nishiyama A, Miura S, Saku K, Urata H. Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension. Am J Physiol Heart Circ Physiol 309: H1987-H1996, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00721.2014.-The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan-and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymasedependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension. mouse; high salt; hypertension; renin-angiotensin system; chymase inhibitor NEW & NOTEWORTHYOur study, for the first time, has provided 1) a new establishment of the salt-sensitive hypertensive mice model, 2) confirmation of direct involvement of chymase-mediated mechanisms proved using a specific chymase inhibitor, and 3) the inhibition of all renin-angiotensin-aldosterone components by a chymase inhibitor.THE ASSOCIATION between high salt (HS) intake and elevated blood pressure has been well established by cross-sectional and longitudinal epidemiological studies. Observational studies and clinical trials performed in the general population have indicated that a higher or lower salt intake is associated with an increase or a decrease of blood pressure, respectively (20, 32). However, the response of blood pressure to changes in salt intake...

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

“…Therefore, we examined the effects of a chymase inhibitor in salt-treated animals. These data are in agreement with previous studies that showed chymase-dependent Ang II generation is associated with the development of hypertension in salt-treated mice (Devarajan et al, 2015). These data are in agreement with previous studies that showed chymase-dependent Ang II generation is associated with the development of hypertension in salt-treated mice (Devarajan et al, 2015).…”

“…Previous studies have shown that salt-induced moderate hypertension was dose-dependently attenuated by a chymase inhibitor in mice (Devarajan et al, 2015). Previous studies have shown that salt-induced moderate hypertension was dose-dependently attenuated by a chymase inhibitor in mice (Devarajan et al, 2015).…”

“…Chymase was originally found in the secretory granules of mast cells (Schick, Austen, & Schwartz, 1984), but has since been detected in the heart, vasculature and kidneys (Miyake-Ogawa et al, 2005). The conversion of Ang I to Ang II is predominantly mediated by chymase instead of ACE in several tissues, for example the vasculature, alimentary tract, skin, kidney and skeletal muscle (Devarajan et al, 2015;Le & Coffman, 2006;Park et al, 2013;Takai, Jin, & Miyazaki, 2012). Moreover, the antihypertensive effects of ACE inhibitors in treating hypertension are not always sufficient because their ability to reduce renal Ang II production is limited (Fox, Guan, Hymel, & Navar, 1992;Maeda et al, 2010).…”

Effect of endothelial microRNAs on blood pressure homeostasis

“…On the other hand, it has been shown that high salt containing water (2% NaCl) intake induced significant elevation of BP and HR two weeks after loading in C57BL/6 male mice 10) . In the present study, when we adopted the high salt water loading (2% NaCl) intervention to our EC-specific heterozygous Dicer KO mice, we did not observe any changes in the hemodynamic parameters of WT C57BL/6 and ECspecific heterozygous Dicer KO female mice.…”

“…Female mice were used for all experiments. In high salt loading experiments, mice were given salt water containing 2% NaCl or normal water 10) . The animal protocols were approved by the Animal Care and Use Committee of the University of Tokyo (P14-047) and Waseda University (2017-A103a).…”