Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/

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...

Inhibiting the Rho-kinase pathway may play a key role in the cardioprotective effect on cardiovascular remodeling associated with eNOS and the oxidative stress-LOX-1 pathway in DS rats, and may be at least a potential therapeutic strategy for hypertension with cardiac hypertrophy.

Myocardial remodeling of DOCA-salt hypertensive rats was significantly ameliorated by subdepressor doses of celiprolol, which may be due to increased eNOS expression in the left ventricle.

Endothelin and growth factors such as transforming growth factor (TGF)-beta1 are important regulators of the cardiovascular system. Although increased production of endothelin-1 (ET-1) and TGF-beta1 have been reported in left ventricular hypertrophy, the detailed roles of these substances in hypertrophy remain to be determined. To elucidate the cardioprotective effects of calcium antagonists in left ventricular hypertrophy, we evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on preproET-1, ET(A) receptor (ETAR) and TGF-beta1 expression in the left ventricle and evaluated the relations between these effects and myocardial remodeling in Dahl salt-sensitive hypertensive (DS) rats fed a high-salt diet. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e., at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy (DSLVH) was noted. Benidipine (DSLVH-B group, n= 8; 1 mg/kg/day, subdepressor dose) or vehicle (DSLVH-V group, n=8) was administered to 6-week-old DS rats for 5 weeks, or until the onset of DSLVH stage, and age-matched (11-week-old) Dahl salt-resistant rats fed the same diet served as a control group (DR-C, n=8). Blood pressure was similar between the DSLVH-B and DSLVH-V groups, but was significantly lower in DR-C rats. The preproET-1, ETAR and TGF-beta1 expressions in the left ventricle were significantly higher in DSLVH-V than in DR-C rats, and significantly lower in DSLVH-B than in DSLVH-V. Benidipine administration resulted in significant improvements in the wall-to-lumen ratio and perivascular fibrosis in the coronary arterioles, and in myocardial fibrosis. We therefore concluded that myocardial remodeling and left ventricular hypertrophy in DS hypertensive rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of benidipine, and that this amelioration was partly due to decreases in the expression of ET-1 and TGF-beta1 in the left ventricle.

Angiotensin II (Ang II) has been shown to stimulate cardiac growth and collagen synthesis in cultured vascular smooth muscle cells and to increase fibroblast proliferation. Chronic infusion with Ang II increases blood pressure and activates growth mechanisms to produce hypertrophy of the heart. This study investigated the effects of an Ang II type 1 receptor antagonist, TCV-116, on preproendothelin-1 (preproET-1), ETA receptor and platelet-derived growth factor (PDGF) A-chain expression in the left ventricle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng x kg(-1) x min(-1)), and the relation of these effects to myocardial remodeling. Rats given Ang II alone (ANGII-V) were compared with rats also receiving TCV-116 (ANGII-TCV). In both groups, blood pressure was similar and significantly higher than in control rats. The preproET-1, ET(A) receptor and PDGF A-chain expressions in the left ventricle were significantly increased in ANGII-V compared with control rats, and were significantly suppressed in ANGII-TCV compared with ANGII-V rats. ANGII-V rats showed a significant increase of the type I collagen expression, wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. Myocardial remodeling in Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose of TCV-116, which may have been due to a decrease in ET-1 and PDGF A-chain expression in the left ventricle.

mass, changes in vessel wall composition, and vascular remodeling. In addition to medial hypertrophy, pressure-overload cardiac hypertrophy with hypertension causes increased vascular and perivascular deposition of collagen (2, 3). Cardiovascular remodeling occurs in a similar sequence of molecular, biochemical, and mechanical events, although the molecular mechanisms have not yet been determined. On the other hand, the activation of cell proliferation by hormones and growth factors has been shown to correlate with the in-

Incisional and ventral hernias are good indications for laparoscopic hernia repair. A successful repair requires complete covering of the hernia defect, adequate tension of the prosthesis, and secure stapling by a hernia stapler. The authors introduce their technique using a double-straight needle device. This technique is easy and quick and achieves adequate fixation between the prosthesis and the abdominal wall, which reduces operating time and provides cosmetic benefit.