Background-Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating ␤-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results-Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (PϽ0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9Ϯ4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22Ϯ8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (PϽ0.005) along with amelioration of heart failure. Conclusions-Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

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In mice carrying the autosomal recessive gene weaver, there is a massive postnatal loss of dopamine in the caudoputamen, the target of the nigrostriatal system, with relative (though not complete) preservation of dopamine in the ventral striatum, a target of the mesolimbic system. There is concomitant death of catecholaminergic neurons in the substantia nigra, with much less cell death in the limbic midbrain area. In the study reported here, we have reexamined the mesostriatal system of weaver mice by means of tyrosine hydroxylase (TH) immunohistochemistry in order to determine the local architecture of the defect within the striatum and substantia nigra. For the dorsal striatum, the most striking finding was the appearance in the weaver caudoputamen of small pockets of especially weak immunostaining within a larger dorsal zone of generally reduced TH-positive neuropil. These pockets were identified as striosomes by calbindin28k and met-enkephalin immunohistochemistry carried out on adjacent sections. In dorsal, central, and caudal sectors of the caudoputamen, there was also more generalized depletion of TH-immunoreactive neuropil. In the mid-brains of the mutants, the patterns of loss of TH-positive neurons appeared to correspond to these distributions of reduced immunostaining in the striatum. In the substantia nigra pars compacta, ventrally situated TH-positive neurons were especially affected, suggesting preferential depletion of TH-positive neurons projecting to striosomes. In addition, there was a central sector of nearly complete loss of TH-positive neurons in the substantia nigra para compacta and a marked depletion of TH-positive neurons in cell group A8 that, together, may have accounted for the diminution of TH-positive innervation of the striatal matrix. We conclude that the effects of the weaver gene discriminate among mesostriatal subsystems not only according to the regional affiliations of these subsystems within the dorsal and ventral striatum, but also according to the preferential association of the subsystems for the striosomal and matrical compartments of the caudoputamen. The depletion of TH-positive innervation was not confined to the dorsal striatum proper. The defect extended into the adjoining nucleus accumbens, where it appeared to affect the lateral "core" division, and included also a lateral part of the olfactory tubercle. Thus, as in the dorsal striatum, the defect in the TH-positive innervation of the ventral striatum closely follows the local architecture of this striatal region. Neuronal loss in the ventral tegmental area was not evident on qualitative analysis, but at the border between lateral cell group A 10 and medial cell group A9 there was obvious loss of immunostained neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Regional distributions of thiobarbituric acid-reactive products, activities of enzymes regulating metabolism of oxygen free radicals, and some of the related enzymes were studied in 10 areas of adult and aged rat brains. Thiobarbituric acid-reactive products were lower in cerebral cortex, septal area, hippocampus, caudate-putamen, and substantia nigra compared with other areas studied in adult rats; however, they increased significantly in the former areas with aging. A slight but significant reduction in superoxide dismutase activity was noted in frontal cortex, septal area, caudate-putamen, and substantia nigra with aging. Glutathione peroxidase and reductase activities were highest in caudate-putamen and in substantia nigra. Glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities were lowest in cortical areas. Phosphofructokinase activity was lowest in septal area and hippocampus in aged rats. Glyceraldehyde-3-phosphate dehydrogenase activity showed only small regional and evolutional changes. Lactate dehydrogenase activity declined with age in most of the areas studied. sn-Glycerol-3-phosphate dehydrogenase activity showed small changes with aging except in hippocampus, where 40% reduction was noted. Generally, cerebral cortical areas, hippocampus, and septal areas were not particularly enriched in enzymes regulating the metabolism of oxygen free radicals. The results were discussed in relation to the role of free radicals in aging.

he rates of cardiovascular or cerebrovascular mortality related to accelerated atherosclerosis are high in patients undergoing chronic hemodialysis (HD) treatment. 1,2 The overall cardiovascular mortality rate in patients undergoing chronic HD treatment is estimated to be approximately 30%, of which 10% are deaths because of myocardial infarction. 3 Recently, it has been shown that monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte chemoattractant and largely responsible for the recruitment of monocytes/macrophages to the vessel wall in the early stage of atherogenesis. [4][5][6][7][8][9][10][11][12] In the clinical setting, it has been reported that the plasma concentrations of several cytokines and chemokines, including MCP-1, increased during long-term HD treatment. 13 However, there have been few studies of the relationship between the severity of human atherosclerosis and the serum concentration of MCP-1 in HD patients. 13,14 High-resolution ultrasound imaging is now a reliable means of directly examining and quantifying pre-clinical Circulation Journal Vol. 68, July 2004 atherosclerotic lesions in peripheral arteries. 15 This method is noninvasive and has high reproducibility. 16 Ultrasound measurements of intimal -medial thickness (IMT) in the carotid artery have been used as indicators of coronary atherosclerosis. 17 Tabara et al reported that the plasma concentration of MCP-1 was significantly associated with IMT in community-based subjects, aged 50 years or older and free from any cardiovascular complications. 18 In the present study, we measured IMT and investigated the effects of MCP-1 and other factors on the severity of IMT in HD patients. We also used immunohistochemistry to investigate the expression of MCP-1 in arterial tissue samples. Methods SubjectsAfter obtaining informed consent, 52 Japanese uremic patients undergoing chronic HD (29 men and 23 women; mean age, 56±10 years: HD group) and 20 age-matched control subjects (9 men and 11 women; mean age, 57±13 years: control group) were enrolled. In the patients undergoing chronic HD, the diagnosed kidney diseases were chronic glomerulonephritis in 47 patients and polycystic kidney disease in 5 patients. To avoid the influence of the cause of the disease, patients with diabetic nephropathy and hypertensive nephrosclerosis were excluded. Patients had been treated by HD 3 times a week for a mean duration of 10.1±7.4 years. The clinical and biochemical characteristics of the patients are summarized in Background Monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, plays an important role in the earliest events of atherogenesis. However, direct evidence of the effects of MCP-1 on atherosclerosis in chronic hemodialysis (HD) patients has not been reported. Methods and ResultsThe serum MCP-1 concentrations and the intimal -medial thickness (IMT) in the carotid arteries were measured in 42 non-diabetic chronic HD patients and 20 age-matched controls. The expression of MCP-1 was examined immunohistochemicall...

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