Chronic Blockade of NO Synthase Activity Induces a Proinflammatory Phenotype in the Arterial Wall

Prevention by Angiotensin II Antagonism

From Unit 460 INSERM, Faculte de Médecine Xavier Bichat (G.L., M.E.P., M.P., F.S., J.-B.M.); Unit 430 INSERM, Hopital Broussais (C.M.); and Unit 141 INSERM, Hopital Lariboisière (D.H.), Paris, France.

Correspondence to Jean-Baptiste Michel, MD, PhD, INSERM U460, Remodelage Cardiovasculaire, UFR de Médecine X. Bichat, 16, rue Henri Huchard, 75870 Paris Cedex 18, France. E-mail U460{at}Bichat.Inserm.fr

Abstract—Chronic blockade of NO production induces hypertension and early occlusive and fibrotic end-stage organ damage owing to vascular lesions in the brain, kidney, and heart. In this study, we evaluated the inflammatory phenotypic changes induced in the arterial wall by chronic N^G-nitro-L-arginine methyl ester (L-NAME) administration and the effect of an angiotensin II receptor (AT₁) antagonist, irbesartan, on these changes. For this purpose, 2 groups of rats received L-NAME in the drinking water (50 mg · kg^-1 · d^-1) for 2 months. One group received no other treatment and the other was treated with irbesartan (10 mg · kg^-1 · d^-1). A third group (controls) received neither L-NAME nor irbesartan. After 8 weeks, plasma, aortas, and left ventricles were sampled from all 3 groups. Expression of inducible NO synthase (iNOS) was evaluated at both the mRNA (quantitative reverse transcription–polymerase chain reaction) and the protein (Western blot and immunohistochemistry) level in the aorta. Expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was evaluated by reverse transcription–polymerase chain reaction, Western immunoblotting, and immunohistochemistry; inflammatory cell infiltration by immunohistochemistry; and fibrosis by Sirius red staining. Chronic L-NAME administration induced the expression of iNOS in the aorta, which was localized in smooth muscle cells as shown by immunohistochemistry and NADPH diaphorase activity. ICAM-1 and VCAM-1 expression was also increased in aortas of L-NAME–treated rats. These phenotypic changes of the vascular wall were associated with inflammatory cell infiltration and fibrosis in the heart. All of these pathological phenomena were prevented by the angiotensin II antagonist irbesartan. The proinflammatory phenotypic changes of the vascular wall induced by blockade of NOS activity could be involved in the interaction between endothelial dysfunction and the development of arteriosclerosis.

Key Words: inducible NO synthase • cell adhesion molecules • macrophages • L-NAME hypertension • AT₁ receptor

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