作者: Ahmad, Sarfaraz ; Ferrario, Carlos M. ; Wright, Kendra N. ; Dell’Italia, Louis J. ; Roberts, Drew J. ; Groban, Leanne ; VonCannon, Jessica L. ; Wang, Hao ; Yamashita, Tomohisa

Bone marrow (BM) Ang II (angiotensin II) is a major participant in the regulation of hematopoiesis and immunity. The novel tissue substrate Ang-(1–12) [angiotensin-(1–12)] and its cleaving enzyme chymase are an essential source of Ang II production in cardiac tissue. We hypothesized this noncanonical chymase-mediated Ang II–producing mechanism exists in the BM tissue. Immunohistostaining and flow cytometry confirmed the presence of Ang-(1–12) immunoreaction in the BM of SD (Sprague Dawley) rats. Chymase-mediated Ang II–producing activity in BM was ≈1000-fold higher than ACE (angiotensin-converting enzyme)-mediated Ang II–producing activity (4531±137 and 4.2±0.3 fmol/min per mg, respectively; n=6; P <0.001) and 280-fold higher than chymase activity in the left ventricle of 16.3±1.7 fmol/min per mg ( P <0.001). Adding a selective chymase inhibitor, TEI-F00806, eliminated almost all 125 I-Ang II production. Flow cytometry demonstrated that delta median fluorescence intensity of chymase in cluster of differentiation 68 positive cells was significantly higher than that in cluster of differentiation 68 negative cells (1546±157 and 222±48 arbitrary units, respectively; P =0.0021). Cluster of differentiation 68 positive and side scatter low subsets, considered to be myeloid progenitors, express the highest chymase fluorescence intensity in rat BM. Chymase activity and cellular expression was similar in both male and female rats. In conclusion, myeloid lineage cells, especially myeloid progenitors, have an extraordinary Ang II–producing activity by chymase in the BM.

2018-11-01·Experimental Physiology

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

Article

作者: Urushihara, Maki ; Fujisawa, Yoshihide ; Nagata, Sayaka ; Hirofumi, Hitomi ; Ansary, Tuba M. ; Urata, Hidenori ; Nakano, Daisuke ; Kagami, Shoji ; Nishiyama, Akira ; Kitamura, Kazuo

New Findings

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.

AbstractThe effects of the selective chymase inhibitor TEI‐F00806 were examined on angiotensin I (Ang I)‐induced hypertension and intrarenal angiotensin II (Ang II) 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) Ang I (1 μg kg−1 min−1, s.c.) + vehicle, and (3) Ang I + TEI‐F00806 (100 mg kg−1 day−1, p.o.) (n = 8–10 per group). Systolic blood pressure was measured weekly using a tail‐cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I 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 Ang II content (P < 0.01) in salt‐treated mice. Treatment with TEI‐F00806 attenuated the development of hypertension (P < 0.001) and decreased Ang II 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.

2015-12-01·American Journal of Physiology-Heart and Circulatory Physiology2区 · 医学

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

2区 · 医学

Article

作者: Uehara, Yoshinari ; Saku, Keijiro ; Miura, Shin-ichiro ; Urata, Hidenori ; Nishiyama, Akira ; Yahiro, Eiji ; Devarajan, Sankar ; Habe, Shigehisa

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 chymase-dependent 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.

100 项与 TPC-806 相关的药物交易

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