Nobuaki Okuda

Chronic Hypoxia Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice

The aim of this study was to investigate the effect of chronic hypoxia on the development and progression of atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice. Male and female apoE-KO mice (6 weeks old) and age- and sex-matched wild-type mice were kept under hypoxic conditions (10.0±0.5% O2) in a gas chamber or in room air for 3 weeks. Aortic atherosclerotic plaque was not observed in wild-type mice under normoxic or hypoxic conditions. In the apoE-KO mice, however, hypoxia induced proliferation of smooth muscle cells and plaque formation in the aorta, which were not observed under normoxic conditions. Although sexual dimorphism of the response to hypoxia was not observed, these hypoxia-induced atherogenic changes were accompanied by a significant increase of plasma low density lipoprotein (LDL) cholesterol and NADPH-dependent vascular superoxide (O2−) production. Furthermore, matrix metalloproteinase (MMP)-9 was activated in the aorta of apoE-KO mice. In conclusion, chronic hypoxia accelerated the development of atherosclerosis in apoE-KO mice, along with increased O2− production and activated MMP-9 in the aorta.

Nifedipine enhances the cardioprotective effect of an angiotensin-II receptor blocker in an experimental animal model of heart failure

This study was designed to examine the hypothesis that a calcium channel blocker nifedipine (CCB) could enhance the cardioprotective effect of an angiotensin-II receptor blocker candesartan (ARB) in the treatment for heart failure. Isoproterenol (ISP) was injected into male rats at 300 mg/kg to produce progressive heart failure. Three months later, the rats were divided into 4 groups and treated for 4 weeks with 1) vehicle (n=20), 2) ARB at 0.2 mg/kg/day (n=6), 3) CCB at 10 mg/kg/day (n=6), or 4) both drugs (n=8). Rats injected with saline served as controls (n=13). ISP caused severe myocardial degeneration and decreased the capillary density (Dcap) of the left ventricular (LV) myocardium (mean±SD: 2,197±627 vs. 2,847 ±298 N/mm2 for normal controls), while increasing plasma thiobarbituric acid-reactive substances (TBARS; 3.6±1.1 vs. 1.9±0.5 nmol/ml). Although ARB therapy preserved cardiac morphology, it had little effect on Dcap or oxidative stress. On the other hand, CCB decreased plasma TBARS and 4-hydroxy-2-nonenal protein expression in LV myocardium. Furthermore, the combination of CCB and ARB increased Dcap and preserved the ultrastructure of LV myocardium, so this combination may be a useful option for the treatment of heart failure.

Efficacy of edaravone, a free radical scavenger, on left ventricular function and structure in diabetes mellitus.

This study was designed to assess the efficacy of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger that possesses anti-oxidant effects, on cardiac function and fine structure of the left ventricular myocardium in diabetes mellitus. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous development of type II diabetes (30 weeks; n = 15) were divided into two groups and treated with edaravone 30 mg/kg/d or vehicle for 2 weeks. OLETF rats showed hyperglycemia (352 ± 71 mg/dl vs normal control; 128 ± 52 mg/dl), increased thiobarbituric acid-reactive substances (TBARS; 6.9 ± 2.5 n M/ml vs 2.8 ± 0.6 n M/ml), and decreased superoxide dismutase activity (21.5 ± 0.9 U/ml vs 25.8 ± 0.7 U/ml). Increased left ventricular end-diastolic pressure (12 ± 3 mm Hg vs 6 ± 2 mm Hg) and hypertrophied cardiocytes (23.1 ± 1.4 vs 17.6 ± 1.0 &mgr;m) were also observed (P < 0.05, respectively). Edaravone could not improve plasma glucose level and hemodynamic parameters but significantly decreased TBARS values (3.8 ± 0.5) and increased superoxide dismutase activity (24.5 ± 0.8) (vs OLETF, P < 0.05, respectively). Moreover, edaravone effectively preserved cardiocyte diameter (18.2 ± 0.9 &mgr;m) and the fine structure of mitochondria. Thus, edaravone exhibits modest cardiac protection in diabetes mellitus independent of blood sugar level.