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...

Abstract-Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogenactivated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase C⑀ (PKC⑀) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKC⑀, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, Ϫ61%; 30 mg, Ϫ78%; and 100 mg, Ϫ84% versus DS; PϽ0.01, respectively) and urinary protein (10 mg, Ϫ78%; 30 mg, Ϫ87%; and 100 mg, Ϫ88% versus DS; PϽ0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKC⑀-MAP kinase-p90RSK pathway, and improvement in endothelial function.

We evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on endothelial cell-type nitric oxide synthase (eNOS) activity and eNOS mRNA expression in the left ventricle (LV) and its relation to coronary flow reserve, and microvascular remodeling in renovascular hypertensive rats (RHR: 2K-1C Goldblatt). Benidipine (5 mg/kg/day) was given to RHR (B-RHR, n = 11) for 6 weeks. Vehicle-treated RHR (U-RHR, n = 11) and age-matched sham-operated rats (ShC, n = 11) served as control group. Coronary flow reserve was measured in conscious rats using colored microspheres. Fifty-micrometer slices of the LV were incubated with L-arginine to measure nitrite production using the Griess method and eNOS mRNA expression was determined by reverse transcription-polymerase chain reaction. An increased blood pressure in RHR was significantly decreased by benidipine. Nitrite production and eNOS mRNA expression in the LV of U-RHR was significantly lower than that of ShC. This suppression of nitrite production and eNOS mRNA expression was significantly reversed in B-RHR. U-RHR demonstrated a significant decrease in coronary flow reserve and capillary density, and a significant increase in wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These impaired factors were improved significantly by benidipine. These findings suggest that benidipine therapy may increase nitrite production and eNOS mRNA expression not only by lessening the endothelial damage by the reduction of blood pressure levels, but also by the stimulation of NOS activity and eNOS mRNA, and this increased NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary flow reserve and microvascular remodeling.

Gas sensing with oxide nanostructures is increasingly important to detect gaseous compounds for safety monitoring, process controls, and medical diagnostics. For such applications, sensor sensitivity is one major criterion. In this study, to sensitively detect volatile organic compounds (VOCs) at very low concentrations, we fabricated porous films using SnO nanocubes (13 nm) and nanorods with different rod lengths (50-500 nm) that were synthesized by a hydrothermal method. The sensor response to H increased with decreasing crystal size; the film made of the smallest nanocubes showed the best sensitivity, which suggested that the H sensing is controlled by crystal size. In contrast, the responses to ethanol and acetone increased with increasing crystal size and resultant pore size; the highest sensitivity was observed for a porous film using the longest nanorods. Using the Knudsen diffusion-surface reaction equation, the gas sensor responses to ethanol and acetone were simulated and compared with experimental data. The simulation results proved that the detection of ethanol and acetone was controlled by pore size. Finally, we achieved ultrahigh sensitivity to ethanol; the sensor response (S) exceeded S = 100 000, which corresponds to an electrical resistance change of 5 orders of magnitude in response to 100 ppm of ethanol at 250 °C. The present approach based on pore size control provides a basis for designing highly sensitive films to meet the criterion for practical sensors that can detect a wide variety of VOCs at ppb concentrations.