ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Current theory holds that peptide hormone action results from hormone binding to cell-surface receptors, with the generation of intracellular second messengers. However, a growing body of evidence suggests that intracellular peptide hormone, either internalized or synthesized in situ, can exert physiologically relevant effects. These effects are diverse and poorly understood. I propose that such intracrine action can serve to modulate cellular function over time and thereby play a role in biological memory of various sorts, in the maintenance of hormonal responsiveness, and in cellular differentiation.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Inhibition of nitric oxide (NO) synthesis withNω-nitro-L-arginine methyl ester (L-NAME) activates vascular angiotensin-converting enzyme (ACE) and causes oxidative stress. We investigated the role of oxidative stress in the pathogenesis of ACE activation in rats. Studies involved aortas of rats receiving no treatment, L-NAME, L-NAME plus L-arginine, or L-NAME plus an antioxidant drug (N-acetylcysteine, allopurinol, or ebselen) for 7 days. L-NAME significantly increased oxidative stress (O2−) and ACE activity. The increased O2−production was normalized by removal of endothelium. Immunohistochemistry showed the increased ACE activity in the endothelial layer. Treatment with antioxidant drugs did not affect the L-NAME-induced increase in systolic arterial pressure but did prevent increases in vascular O2−production and ACE activity. These results implicate oxidative stress in the pathogenesis of vascular ACE activation in rats with long-term inhibition of NO synthesis. The observed effects of antioxidant drugs on ACE activation do not appear to involve the hypertension induced by L-NAME.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Previous studies have suggested that salt-sensitive hypertension in humans and experimental animals may in part be due to dysregulation of the L-arginine/nitric oxide system. This study was conducted to determine the endothelial, inducible, and neuronal nitric oxide synthase expressions in the kidney, heart, aorta, and brain of salt-sensitive and salt-resistant Dahl rats. We studied salt-sensitive and salt-resistant Dahl rats maintained on high- (8%) and regular- (0.2%) salt diets for 3 weeks. Blood pressure was modestly elevated in both Dahl salt-sensitive and salt-resistant rats consuming regular diet and severely increased in sensitive but not resistant rats consuming the high-salt diet. The Dahl salt-sensitive animals showed a significant reduction in kidney, heart, and aorta inducible nitric oxide synthase protein abundance on the regular diet, with further reductions on the high-salt diet. In addition, the high-salt diet markedly downregulated endothelial nitric oxide synthase expression in the kidney and aorta but not in the heart of the Dahl salt-sensitive animals. The rise in blood pressure in the Dahl salt-sensitive rats on the high-salt diet was accompanied by a significant elevation of brain neuronal nitric oxide synthase protein. In contrast, salt-resistant animals showed no change in heart, kidney, and aorta endothelial or brain neuronal nitric oxide synthase and considerably less intense changes in inducible isotype than that seen in the salt-sensitive group in response to the high-salt diet. In conclusion, the study revealed a marked downregulation of inducible nitric oxide synthase in the Dahl salt-sensitive rats on the regular diet, with further reductions on the high-salt diet. Furthermore, Dahl salt-sensitive rats consuming the high-salt diet showed significant reductions of kidney and aorta endothelial nitric oxide synthase and an upregulation of brain neuronal nitric oxide synthase expression.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We recently showed elevated reactive oxygen species (ROS), reduced urinary excretion of NO metabolites (NOx), and increased NO sequestration as nitrotyrosine in various tissues in rats with lead-induced hypertension. This study was designed to discern whether the reduction in urinary NOx in lead-induced hypertension is, in part, due to depressed NO synthase (NOS) expression. Male Sprague-Dawley rats were randomly assigned to a lead-treated group (given lead acetate, 100 ppm, in drinking water and regular rat chow), a group given lead and vitamin E-fortified chow, or a normal control group given either regular food and water or vitamin E-fortified food for 12 weeks. Tail blood pressure, urinary NOx excretion, plasma malondialdehyde (MDA), and endothelial and inducible NOS (eNOS and iNOS) isotypes in the aorta and kidney were measured. The lead-treated group exhibited a rise in blood pressure and plasma MDA concentration, a fall in urinary NOx excretion, and a paradoxical rise in vascular and renal tissue eNOS and iNOS expression. Vitamin E supplementation ameliorated hypertension, lowered plasma MDA concentration, and raised urinary NOx excretion while significantly lowering vascular, but not renal, tissue eNOS and iNOS expression. Vitamin E supplementation had no effect on either blood pressure, plasma MDA, or NOS expression in the control group. The study also revealed significant inhibition of NOS enzymatic activity by lead in cell-free preparations. In conclusion, lead-induced hypertension in this model was associated with a compensatory upregulation of renal and vascular eNOS and iNOS expression. This is, in part, due to ROS-mediated NO inactivation, lead-associated inhibition of NOS activity, and perhaps stimulatory actions of increased shear stress associated with hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (M&OV0312;O2) via a B2-kinin receptor/nitric oxide-dependent mechanism. Left ventricular free wall and septum were isolated from normal and B2-kinin receptor knockout (B2−/−) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline M&OV0312;O2was not significantly different between normal (239±13 nmol of O2· min−1· g−1) and B2−/− (263±24 nmol of O2· min−1· g−1) mice. S-nitroso-N-acetyl-penicillamine (10−7to 10−4mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36±3%) and B2−/− mice (28±3%). This was also true for the endothelium-dependent vasodilator substance P (10−10to 10−7mol/L; 22±7% in normal mice and 20±4% in B2−/− mice). Bradykinin (10−7to 10−4mol/L), ramiprilat (10−7to 10−4mol/L), and amlodipine (10−7to 10−5mol/L) all caused concentration-dependent decreases in M&OV0312;O2in normal mice. At the highest concentration, tissue O2consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in M&OV0312;O2to all 3 drugs was attenuated in the presence of NG-nitro-L-arginine-methyl ester. However, in the B2−/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on M&OV0312;O2. Therefore, nitric oxide, through a bradykinin-receptor-dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B2−/− mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Upregulation of endothelial adhesion molecules is the earliest step of atherogenesis. Whether obesity induces endothelial adhesin upregulation is unknown. To address this topic, circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor (vWF) concentrations were evaluated in 22 obese hypertensive (51.4±4.6 years [mean±SD age]), 19 obese normotensive (50.6±3.8 years), 18 nonobese hypertensive (52.3±3.9 years), and 16 nonobese normotensive (52.4±3.5 years) men without other risk factors or overt atherosclerosis. All measurements were repeated in the obese subgroups after weight loss induced by 12 weeks of caloric restriction. Basal circulating VCAM-1 levels were similar between the 2 obese groups but were higher (P<0.0001) than in the 2 nonobese groups. No differences were found between nonobese hypertensives and normotensives. Serum low density lipoprotein cholesterol was weakly correlated with plasma soluble VCAM-1 levels in pooled, obese subjects (r=0.362,P=0.02). Plasma soluble adhesin and vWF concentrations decreased significantly after weight loss in obese hypertensives (VCAM-1P=0.03, ICAM-1P=0.004, E-selectinP<0.0001, and vWFP=0.003) and normotensives (VCAM-1P=0.04, ICAM-1P=0.003, E-selectinP<0.0001, and vWFP<0.0001). Body mass index was correlated with plasma E-selectin concentrations at baseline and after weight loss in obese hypertensives (r=0.501,P=0.018 andr=0.466,P=0.03, respectively) and obese normotensives (r=0.523,P=0.021 andr=0.460,P=0.05, respectively). In conclusion, our data show that obesity per se induces early endothelial activation in hypertensive and normotensive men. Weight loss counteracted endothelial activation in both obese hypertensive and normotensive men.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The effect ofN-acetyl-L-cysteine on interleukin-1β-induced nitric oxide synthase expression was studied in rat vascular smooth muscle cells to determine if the reduction/oxidation state would modulate cytokine-induced changes. Interleukin-1β induced the production of nitrite, a stable metabolite of nitric oxide in a time- and dose-dependent manner. Cytokine-induced nitrite production was enhanced by the addition ofN-acetyl-L-cysteine in a dose-dependent manner, with a >50% increase produced by the addition of 1 mmol/LN-acetyl-L-cysteine. There was no influence on nitrite production when the cells were treated withN-acetyl-L-cysteine alone. Northern and Western blot analyses revealed that the upregulation of interleukin-1β-induced nitric oxide production byN-acetyl-L-cysteine resulted from an enhanced expression of inducible nitric oxide synthase. Interferon-γ or tumor necrosis factor-α when used alone had no influence on nitrite production in the absence or presence ofN-acetyl-L-cysteine. Nitrite accumulation was higher by the cells treated with interleukin-1β combined with either interferon-γ or tumor necrosis factor-α compared with those treated with interleukin-1β alone.N-Acetyl-L-cysteine upregulated nitrite production and inducible nitric oxide synthase expression induced by combination treatment with interleukin-1β and either interferon-γ or tumor necrosis factor-α. However,N-acetyl-L-cysteine had no significant influence in cytokine-induced activation of nuclear factor-κB or signal transducer and activator of transciption-1, as assessed by electrophoretic mobility shift assays. These results demonstrate thatN-acetyl-L-cysteine possibly acted as a thiol-containing reducing agent and facilitated the expression of inducible nitric oxide synthase in rat vascular smooth muscle cells by cytokines through a mechanism that is independent of nuclear factor-κB or signal transducer and activator of transciption-1.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

To examine the relationship between diet, blood pressure, and plasma insulin concentrations, we studied 14 healthy males who were prescribed low-fat and high-fat diets. The low-fat diet contained 25% (of energy intake) fat and 54% carbohydrate; the high-fat diet was 45% fat (predominantly saturated fat) and 36% carbohydrate. The diets were consumed over consecutive 2-week periods in random sequence, separated by a 2-week washout period. Resting supine systolic and diastolic blood pressures decreased significantly by 7 and 3 mm Hg, respectively, and plasma total cholesterol, LDL cholesterol, and HDL cholesterol concentrations all fell (by 21.6%, 25.7%, and 18.0%, respectively; allP<0.001) on the low-fat compared with the high-fat diet. Fasting glucose and the glucose area under the curve during the frequently sampled intravenous glucose tolerance test (300 mg/kg glucose load with blood sampling for 180 minutes) were significantly lower, and the glucose disappearance rate tended to be faster after the low-fat diet. In contrast, fasting insulin concentrations and the insulin response (insulin area under the curve) to glucose challenge were unchanged. Insulin sensitivity (defined as the rate of glucose disappearance per unit of insulin increase during the period 0 to 40 minutes after the glucose load) was significantly higher on the low-fat diet. These results suggest that the hypotensive effects of a low-fat, high-carbohydrate diet, although associated with an improvement in insulin sensitivity, are not mediated by changes in plasma insulin concentration.

ISSN:0194-911X    

出版商:OVID    

年代:1999

数据来源: OVID