Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene.
We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate-salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the Ren-1 gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg. kg(-)(1). d(-)(1)) and an angiotensin type 1 (AT(1)) receptor antagonist (L-158809, 4 mg. kg(-)(1). d(-)(1)) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128+/-2 mm Hg) compared with controls (109+/-2 mm Hg) (P:<0.001), while plasma renin concentration was decreased by 97% (P:<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (P:<0.001). Urinary albumin (P:<0.05) and proliferating cell nucleic antigen-positive cells in the tubules and interstitium of the renal cortex (P:<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT(1) antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT(1) antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT(1) antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT(1) antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.
Peng
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Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202, USA.
Carretero
O A
OA
Alfie
M E
ME
Masura
J A
JA
Rhaleb
N E
NE
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D003094:Collagen / Q000032:analysis; D003900:Desoxycorticosterone; D006973:Hypertension / Q000097:blood / Q000517:prevention & control* / Q000652:urine; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood / Q000172:deficiency / Q000235:genetics; D012965:Sodium Chloride; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D018809:Proliferating Cell Nuclear Antigen; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C070967:L 158809; D003094:Collagen; D012083:Renin; D017257:Ramipril