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(Hypertension. 1999;34:496-502.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Long-Term Inhibition of Renin-Angiotensin System Sustains Memory Function in Aged Dahl Rats

Nobuhito Hirawa; Yoshio Uehara; Yukari Kawabata; Atsushi Numabe; Tomoko Gomi; Toshio Ikeda; Tsutomu Suzuki; Atsuo Goto; Teruhiko Toyo-oka; Masao Omata

From the Health Service Center and Department of Medicine, University of Tokyo (Y.U., Y.K., A.G., T.T.-o., M.O.); the 2nd Department of Medicine, Yokohama City University (N.H.); Division of Clinical Pathology, Dokkyo University School of Medicine (A.N.), Mibu; Department of Nephrology, NTT Kantoh-Teishin Hospital (T.G., T.I.), Tokyo; and the Department of Toxicological Sciences, Hoshi University (T.S.).

Correspondence to Yoshio Uehara, MD, Health Service Center and Department of Medicine #2, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail uehara-2im{at}h.u-tokyo.ac.jp

Abstract—The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 µg/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 µg/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CA1 regions compared with those in the untreated DS. Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

Key Words: cilazapril • angiotensin-converting enzyme inhibitors • receptors, angiotensin • memory • cognition • rats, aging • aging

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