Published Online
on September 8, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on February 4, 2003
Revised on February 27, 2003

Important Role of Nitric Oxide in the Effect of Angiotensin-Converting Enzyme Inhibitor Imidapril on Vascular Injury

Rui Chen; Masaru Iwai; Lan Wu; Jun Suzuki; Li-Juan Min; Tetsuya Shiuchi; Takashi Sugaya; Hong-Wei Liu; Tai-Xing Cui; and Masatsugu Horiuchi^*

From the Department of Medical Biochemistry, Ehime University School of Medicine (R.C., M.I., L.W., J.S., L.-J.M., T.Shiuchi, H.-W.L., T.-X.C., M.H.), Shigenobu, Ehime, Japan; and Discovery Research Laboratory, Tanabe Seiyaku Co (T.Sugaya), Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

Abstract--To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT₁a-receptor-deficient (AT₁aKO) mice. A polyethylene cuff was placed around the femoral artery of AT₁aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)- was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF- were attenuated in the injured artery in AT₁aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF- in AT₁aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT₁aKO mice. Treatment with imidapril did not change AT₂ receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.

Key words: nitric oxide • angiotensin • vasculature • arteries

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