ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-&agr;, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-&bgr;, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors acting as transcription factors on numerous target genes after heterodimerization with the retinoid X receptor. PPAR-&agr; and PPAR-&ggr; may be activated by different agonists, although the endogenous ligands are unknown. Although PPAR-&agr; is mainly involved in fatty acid oxidation and expressed in liver, kidney, and skeletal muscle, and PPAR-&ggr; is mainly involved in fat cell differentiation and insulin sensitivity, both are expressed in smooth muscle cells and myocardium, although PPAR-&ggr; are scarce in the latter. Activators of PPAR-&agr; such as fatty acids and fibrates, and PPAR-&ggr; such as thiazolidinediones have been shown to exert antiproliferative effects, antagonize angiotensin II actions in vivo and in vitro, and exert antioxidant actions inhibiting generation of reactive oxygen species and activation of inflammatory mediators on blood vessels and the heart. These agents lowered blood pressure in several models of hypertension and corrected endothelial dysfunction. They exerted anti-inflammatory and antifibrotic actions on blood vessels and the heart. With the development of dual &agr;/&ggr;-PPAR activators, these newer agents may become interesting therapeutic agents for prevention of vascular and cardiac complications of hypertension as well as for preventative therapy in other forms of cardiovascular disease.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation orN-hydroxy-N′-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by ≈90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470±21 to 570±41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—The thick ascending limb of the loop of Henle (THAL) plays an essential role in the regulation of sodium and water homeostasis by the kidney. l-Arginine, the substrate for nitric oxide synthase (NOS), decreases NaCl absorption by THALs. We hypothesized that eNOS produces the NO that regulates THAL NaCl transport and that selective expression of eNOS in the THAL of eNOS knockout(−/−) mice would restore the effects of l-arginine on NaCl absorption. eNOS−/− mice were anesthetized, the left kidney was exposed, and the renal interstitium was injected with recombinant adenoviral vectors that expressed green fluorescent protein (GFP) or eNOS driven by the promoter of the Na/K/2Cl cotransporter Ad-NKCC2GFP and Ad-NKCC2eNOS, respectively. In Ad-NKCC2eNOS–transduced kidneys, eNOS expression was detected 7 days after injection but was absent in Ad-NKCC2GFP–transduced kidneys. In THALs from eNOS−/− mice transduced with Ad-NKCC2eNOS, adding l-arginine increased DAF-2DA fluorescence, a measure of NO production, by 9.1±1.1% (P<0.05; n=5), but not in THALs transduced with Ad-NKCC2GFP. In THALs from eNOS−/− mice transduced with Ad-NKCC2eNOS, Cl absorption averaged 85.9±11.8 pmol/min per millimeter. Adding l-arginine (1 mmol/L) to the bath decreased Cl absorption to 59.7±11.0 pmol/min per millimeter (P<0.05; n=6). In THALs transduced with Ad-NKCC2GFP, Cl absorption averaged 96.0±21.0 pmol/min per millimeter. Adding l-arginine to the bath did not significantly affect Cl absorption (100.6±20.6 pmol/min per millimeter; n=4). We concluded that gene transfer of eNOS to the THAL of eNOS−/− mice restores l-arginine–induced inhibition of NaCl transport and NO production. These data indicate that eNOS is essential for the regulation of THAL NaCl transport by NO.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—We examined the effects of heme administration (15 mg/kg IV) on indexes of renal carbon monoxide production and contrasted the renal functional response to heme in anesthetized rats pretreated and not pretreated with stannous mesoporphyrin (40 &mgr;mol/kg IV) to inhibit heme oxygenase or sodium meclofenamate (5 mg/kg IV plus infusion at 10 &mgr;g/kg per minute) to inhibit cyclooxygenase. In rats without drug pretreatment, heme administration decreased renal vascular resistance and increased renal blood flow, urine volume, and sodium excretion associated with augmented urinary excretion of 6-keto-PGF1&agr;and enhanced concentration of carbon monoxide in the renal cortical microdialysate. Pretreatment with stannous mesoporphyrin did not prevent heme from producing renal vasodilation and increasing renal blood flow but abolished the diuretic and natriuretic responses. Conversely, pretreatment with sodium meclofenamate blunted the renal vasodilatory effect of heme but affected neither the diuretic nor the natriuretic effect. We conclude that heme-induced renal vasodilation is a cyclooxygenase-dependent response involving increased synthesis of PGI2, whereas heme-induced diuresis and natriuresis are heme oxygenase-dependent responses involving inhibition of tubular reabsorption of sodium and water through undefined mechanisms.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—We investigated the association of &bgr;2 adrenoceptor functional gene variants (Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms), obesity phenotypes, and blood pressure levels in a large, ethnically mixed urban population. The individuals (n=1576) were randomly selected for a cross-sectional study of cardiovascular risk factors in Vitória, Brazil. Statistically significant associations among systolic blood pressure and the Arg16Gly and Thr164Ile variants were identified in univariate analysis. The Gly16/Gly16 genotype was still associated with systolic blood pressure (SBP) in multivariate analysis adjusting for age, gender, ethnicity, total cholesterol, diabetes, and body mass index (BMI) (P=0.01). The Arg16 allele was the only genotypic variable associated with BMI, and, in a dominant model, it remained associated with an increased BMI even after adjustment for age, gender, ethnicity, triglycerides, HDL cholesterol, LDL cholesterol, diabetes, and hypertension status (P=0.02). Although the different polymorphisms did not interact in the determination of SBP, a significant interaction with BMI (P=0.02), not through linkage disequilibrium, was identified between the Gln27Glu and the Thr164Ile variants. Furthermore, a significant interaction among the Arg16Gly polymorphism and BMI (P=0.036) and waist-hip ratio (P=0.003) in determining SBP was disclosed by ANOVA factorial modeling, with SBP used as the dependent variable. An interaction between the Thr164Ile polymorphism and waist-hip ratio was also identified (P=0.018). Finally, multiple logistic regression models showed a 1.48-fold increase in the risk of hypertension in individuals harboring the Gly16/Gly16 genotype and a 1.31-fold (P=0.01) and a 1.49-fold (P=0.003) increased risk of obesity in individuals harboring the Gln27/Gln27 genotype or the presence of the Arg16 allele, respectively. Taken together, these data provide evidence for a strong but complex relation between &bgr;-adrenoceptor gene variants, hypertension, and obesity.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Abstract—We have previously described angiotensin I-converting enzyme (ACE) forms in urine of normotensive (190 and 65 kDa) and hypertensive patients (90 and 65 kDa, N-domain ACEs). Based on the results described above, experimental and genetic models of hypertension were investigated to distinguish hemodynamic and genetic influence on the generation of ACE profile in urine: Wistar-Kyoto and Brown Norway rats (WKY and BN), spontaneously and stroke-prone spontaneously hypertensive rats (SHR and SHR-SP), one kidney/one clip rats (1K1C), deoxycorticosterone acetate (DOCA) salt-treated and untreated rats, and enalapril-treated SHR (SHRen). Two peaks with ACE activity were separated from the urine of WKY and BN rats submitted to an AcA-44 column, WK-1/BN-1 (190 kDa), and WK-2/BN-2 (65 kDa), as described for urine of normotensive subjects. The same results were obtained for urine of 1K1C and DOCA salt-treated and untreated rats, analyzed to evaluate the influence of hemodynamic factors in the ACE profile in urine. The urine from SHR, SHR-SP, and SHRen presented 80 (S-1, SP-1, Sen-1) and 65 (S-2, SP-2, Sen-2) kDa ACE forms, differing from the urine profile of normotensive rats, but similar to that described for hypertensive patients. The presence of 80 kDa ACE in urine of SHR, SHR-SP, and SHRen and its absence in urine of experimental hypertensive rats (1K1C and DOCA salt) support the hypothesis that this enzyme could be a possible genetic marker of hypertension. Taken together, our results provide evidence that ACE forms with 90/80 kDa isolated from the urine of hypertensive subjects and genetic hypertensive animals behaves as a possible genetic marker of hypertension and not as a marker of high blood pressure.

ISSN:0194-911X    

出版商:OVID    

年代:2003

数据来源: OVID