Abstract-Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific  1 -antagonist with weak  2 -agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-B (NF-B), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-B phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-B, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-1 gene expression. Key Words: receptors, adrenergic,  Ⅲ adrenergic receptor blockers Ⅲ kinase Ⅲ nitric oxide Ⅲ oxidative stress Ⅲ cell adhesion molecules L eukocyte adhesion to the endothelium and infiltration into tissue have been found to contribute to the tissue damage and impairment of vascular perfusion in a broad array of systemic diseases, including atherosclerosis and hypertension. 1 Localized accumulation of leukocytes is mediated by the endothelial expression of specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, or plateletendothelial cell adhesion molecule-1. 2 VCAM-1 is an early marker of endothelial activation and dysfunction, leukocyte infiltration, and vascular remodeling, and a recent study demonstrated that VCAM-1 plays a key role in early atherogenesis. 3 Endothelium-derived relaxing factor, nitric oxide (NO), is an important component of vascular homeostasis. 4 Recently, some investigators 5,6 have shown that the serine/ threonine kinase Akt, a downstream effector of phosphatidylinositol 3-OH kinase (PI3K), phosphorylates human endothelial NO synthase (eNOS) on serine 1177 in response to varied stimuli, such as growth factors and shear stress. Furthermore, expression of adhesion molecules, including VCAM-1, can be regulated by NO, and increased levels of NO are associated with decreased leukocyte adhesion molecule expression. 7 The mechanisms by which NO modulates expression of VCAM-1 are unclear. However, regulation of VCAM-1 expression...