title: Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension.
abstract: 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.
authors.affiliation: Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, Fukuoka, Japan;
authors.forename: Sankar
authors.initials: S
authors.lastname: Devarajan
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan;
authors.forename: Eiji
authors.initials: E
authors.lastname: Yahiro
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan;
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Parasitology, Fukuoka University School of Medicine, Fukuoka, Japan; and.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Habe
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan;
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan;
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
authors.affiliation: Department of Cardiovascular Diseases, Fukuoka University Chikushi Hospital, Fukuoka, Japan; uratah@fukuoka-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Urata
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000450:Aldosterone / Q000097:blood / Q000652:urine; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D017673:Sodium Chloride, Dietary; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004232:Diuretics; D000451:Mineralocorticoid Receptor Antagonists; D015842:Serine Proteinase Inhibitors; D017673:Sodium Chloride, Dietary; D000808:Angiotensinogen; D000804:Angiotensin II; D000450:Aldosterone; D053818:Chymases
keywords: chymase inhibitor; high salt; hypertension; mouse; renin-angiotensin system