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(Hypertension. 2004;43:499.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis

Keisuke Tokuda; Hisashi Kai; Fumitaka Kuwahara; Hideo Yasukawa; Nobuhiro Tahara; Hiroshi Kudo; Kiyoko Takemiya; Mitsuhisa Koga; Tomoka Yamamoto; Tsutomu Imaizumi

From the Department of Internal Medicine III and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.

Correspondence to Hisashi Kai, MD, PhD, FAHA, Internal Medicine III and Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail naikai{at}med.kurume-u.ac.jp

Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day -7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-ß expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-ß and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1–mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.

Key Words: angiotensin II • fibrosis • hypertension, experimental • macrophages • inflammation

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