摘要:

ObjectiveAssociation between blood pressure and triglyceride levels, and between lipoprotein lipase (LPL) (C/G)447polymorphism and triglyceride levels has been described. We investigated whether the LPL (C/G)447polymorphism was associated with blood pressure (BP) levels and longitudinal changes.Design and participantsFor cross-sectional analysis, 767 men and 816 women (29–55 years) were selected from the Stanislas Cohort, a cohort of volunteers for a free health check-up. Only subjects without anti-hypertensive or lipid-lowering medication were included in the study. A subset of this sample population, 359 men and 337 women, had been followed during the 11 years prior to recruitment in the Stanislas Cohort and was used for longitudinal analysis.ResultsThe cross-sectional study showed that serum triglyceride levels differed significantly according to LPL genotypes in both genders, the G447 allele being associated with the lowest triglyceride levels (P≤ 0.01). Univariate and multivariate analysis found that LPL polymorphism was not related to BP levels in men. In contrast, women with the LPL-G447 allele had lower systolic (SBP) and pulse (PP) pressure levels than those with the LPL-CC genotype (P≤ 0.01 andP≤ 0.05, respectively); this association being independent of triglyceride level. The longitudinal study showed LPLgenotype was an independent predictor of PP and SBP follow-up levels in women; changes over 11 years being lower for LPL-G447 allele carriers (P≤ 0.05). These associations were independent of triglyceride level.ConclusionThe LPL-G447 allele was found associated with lower PP and SBP independently of triglyceride level in women. This result suggests that the LPL gene may influence blood pressure.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo compare coronary dilation in uninephrectomized hypertensive deoxycorticosterone acetate (DOCA)-salt rats (HTRs), treated for 2 or 4 weeks, with age-matched uninephrectomized normotensive rats (NTRs).Design and methodsCoronary perfusion pressure was recorded in isolated hearts perfused at a constant flow rate to evaluate coronary resistance.ResultA decreased vasoconstriction due to NG-nitro-L-arginine (NNLA, 30 μmol/l) in hearts from HTRs suggested a reduced basal nitric oxide (NO) release. In contrast, coronary vasodilation due to the NO donor, sodium nitroprusside (3 μmol/l), remained unaffected in 2-week HTRs, and was enhanced in 4-week HTRs. Cumulative dose-response curves to bradykinin induced an important vasodilation in NTRs, with a maximal response that remained unaffected in the presence of either NNLA (30 μmol/l), indomethacin (10 μmol/l) or the two combined. In contrast, hearts from HTRs showed a diminished maximal relaxation to bradykinin, suggesting an altered endothelium-dependent relaxation. The presence of NNLA or indomethacin had no effect on the weak relaxation observed in HTRs. However, NNLA and indomethacin combined unmasked an important relaxation due to bradykinin in HTRs. The addition of clotrimazole (1 μmol/l) to NNLA and indomethacin blunted the relaxation due to bradykinin in both NTRs and HTRs. Perfusion with superoxide dismutase (120 IU/ml) restored most of the coronary relaxation due to bradykinin in hearts from HTRs. Bradykinin-induced prostaglandin I2(PGI2) and E2(PGE2) production was unaffected by hypertension. No increase in thromboxane A2(TXA2) due to bradykinin was detected. Finally, reduced reactivity to papaverine and forskolin was observed in hearts from HTRs.ConclusionDOCA-salt hypertension is associated with alterations in coronary reactivity. Basal NO formation appears to be reduced in HTRs, but the intact relaxation to exogenous NO suggests a preserved guanylate cyclase pathway. In addition, alteration in adenylate cyclase activity, and not in prostaglandin production, may explain the blunted cAMP-mediated responses in HTRs. The combined nitric-oxide synthase (NOS) and cyclo-oxygenase (COX) inhibition unmasked an endothelium-derived hyperpolarizing factor (EDHF) involvement in the coronary dilation due to bradykinin in hearts from HTRs, suggesting that endothelial NO and PGI2, although unable to induce coronary smooth-muscle relaxation, can inhibit EDHF production in HTRs. Impairment in the adenylate cyclase pathway and the suppression of NO by free radicals may explain the blunted vasodilation in DOCA-salt hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveChronic inhibition of nitric oxide (NO) synthesis by Nω-nitro-L-arginine methyl ester (L-NAME) increases vascular tissue angiotensin II activity and oxidative stress in animals by incompletely understood mechanisms. In a rat model, we investigated the role of local angiotensin II activity in the pathogenesis of increased oxidative stress.DesignWe studied the aortas of control rats and others receiving L-NAME or L-NAME plus an angiotensin II type 1 receptor antagonist (CS-866).ResultsAdministration of L-NAME for 7 days significantly increased superoxide anion (O2−) and both immunoreactivity and electrophoretically demonstrable activity of redox-sensitive transcription factors (NF-κB and AP-1). Treatment with the angiotensin II type 1 receptor antagonist prevented all of the above changes. The observed effects of the type 1 receptor antagonist was independent of the L-NAME-induced arterial hypertension.ConclusionsThese findings suggest that chronic inhibition of NO synthesis may increase vascular oxidative stress and oxidative stress-sensitive signals via the action of angiotensin II mediated via type 1 receptors.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the effects of hypertension and exercise on interleukin-6 (IL-6) levels and mononuclear cell adhesion to endothelial cells.DesignTwelve hypertensive and 33 normotensive volunteers were studied prior to and following exhaustive exercise. End points were stimulated IL-6 levels and peripheral blood mononuclear cell (PBMC) CD11a (LFA-1) expression andin vitroPBMC adhesion to human umbilical venous endothelial cells (HUVEC).ResultsIn response to exercise, all subjects showed a significant increase in lymphocyte CD11a density and in IL-6 levels (P< 0.001). Compared to normotensives, hypertensives showed significantly greater mean density of CD11a on lymphocytes (P< 0.05) and on monocytes (P< 0.05). In response to exercise, hypertensive subjects showed a twofold greater increase in IL-6 as compared to normotensives (+ 240 pg/ml versus + 123 pg/ml, respectively;P< 0.05). PBMC adhesion to HUVEC was increased in hypertensives but decreased in normotensives following exercise (P< 0.03).ConclusionThe findings suggest that exercise leads to increased mononuclear cell adhesion to endothelial cells in patients with hypertension, possibly through cytokine-induced activation of mononuclear cell CD11a. These findings, coupled with prior data indicating increased endothelial activation in hypertension, may be relevant to the increased risk of atherosclerosis in human hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundIn two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model.MethodsWe analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney.ResultsLong-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment.ConclusionsThe present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETAreceptor antagonist, J-105859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to conFIrm the potential of this compound as an ETAantagonist.MethodsVehicle and J-105859 were administered to saltloaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-105859.ResultsThe Kivalues of J-105859 for cloned human ETAand ETBwere 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2= 10.08) and BQ-3020 (ETBagonist)-induced contractions in pulmonary artery (pA2= 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-105859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-105859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-105859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day.ConclusionJ-105859 is a selective, potent, orally active ETA-selective antagonist. ETAantagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo investigate the expression of hepatocyte growth factor (HGF) – a multifunctional factor implicated in tissue regeneration, wound healing and angiogenesis – that is induced by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs), using coculture of human VSMCs and cells of the human monocytoid cell line, THP-1.MethodsWe collected supernatant from the coculture medium and measured HGF concentrations with an enzyme-linked immunosorbent assay. Northern blot analysis of HGF mRNA was performed using a specific cDNA. To explore which types of cells produce HGF, we performed immunohistochemistry.ResultsCoculture of VSMCs with THP-1 cells for 24 h caused a fivefold increase in HGF concentrations over that in control VSMC culture. Northern blot analysis showed an induction of HGF mRNA in the coculture with a peak at 3 h. Separated cocultures demonstrated that both direct contact and soluble factors contribute to the production of HGF. Immunohistochemistry demonstrated that both types of cells in the coculture produce HGF. Neutralizing antibodies against tumor necrosis factor (TNF)-α interleukin (IL)-1β and IL-6 inhibited the HGF production in THP-1 cells and VSMCs that was induced by the coculture conditioned medium. The protein kinase C inhibitors H-7, calphostin C and K252b, and the tyrosine kinase inhibitor, genistein, signifcantly inhibited the production of HGF in the coculture.ConclusionsCell-to-cell interactions between monocytes and VSMCs induced HGF synthesis in both types of cells, suggesting that local HGF production induced by this cell-to-cell interaction has an important role in the pathogenesis of hypertension, atherosclerosis or vascular remodelling.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesA recent study demonstrated that reactive oxygen species (ROS) were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). However, the role of oxidative stress in hypertension and its related diseases in SHRSP remains unknown. To determine whether phytoestrogens attenuate oxidative DNA damage in vascular smooth muscle cells (VSMC) from SHRSP and Wistar-Kyoto (WKY) rats, we investigated the effect of daidzein, genistein and resveratrol on oxidative DNA damage in VSMC, induced by advanced glycation end-products (AGEs).MethodsVSMC were treated with AGEs in the presence or absence of phytoestrogens for the indicated time. Cellular degeneration induced by AGEs was characterized in terms of intracellular oxidant levels, intracellular total glutathione (GSH) levels, mRNA expression for γ-glutamylcysteine synthetase (GCS), and a new marker of oxidative stress, 8-hydroxy-2′-deoxyguanosine (8-OHdG) contents.ResultsAGEs stimulated 8-OHdG formation in VSMC in a time- and dose-dependent manner. We also confirmed that VSMC from SHRSP were more vulnerable to oxidative stress induced by AGEs, than VSMC from WKY rats. Daidzein, genistein or resveratrol reduced AGEs-induced 8-OHdG formation in a dose-dependent manner. The preventive effects of phytoestrogens on 8-OHdG formation remarkably paralleled changes in the intracellular oxidant levels in VSMC following AGEs treatment. We further demonstrated that phytoestrogens increase intracellular total GSH level in VSMC. Increased GSH synthesis was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, GCS. Phytoestrogens-stimulated total GSH level in VSMC could lead to decreased intracellular oxidant levels, and thus prevent oxidative DNA damage, induced by AGEs. The phytoestrogens are powerful antioxidants able to interfere with AGEs-mediated oxidative DNA damage of VSMC, and are potentially useful against vascular diseases where ROS are involved in hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesIn the present study, we evaluated the effect of angiotensin-(1–7) [Ang-(1–7)] and its selective antagonist, D-Ala7-Ang-(1–7) (A-779), at the nucleus tractus solitarii (nTS), in the modulation of the bradycardic component of the baroreceptor reflex.MethodsMean arterial pressure (MAP) and heart rate were continuously recorded. Reflex changes in heart rate elicited by bolus injection of graded doses of phenylephrine were evaluated before and after bilateral microinjection (glass micropipette) of Ang-(1–7) (10 pmol or 25 pmol), A-779 (50 pmol) or saline (vehicle) into the nTS of urethane anesthetized male Wistar rats or spontaneously hypertensive rats (SHR). The averaged ratio between reflex changes in heart rate and changes in MAP was used as index of baroreflex sensitivity.ResultsMicroinjection of Ang-(1–7) into the nTS elicited significant decreases in MAP and heart rate in both Wistar and SHR. While the decrease in MAP was similar in both strains, the changes in heart rate were smaller in SHR. A- 779 produced small changes in MAP and heart rate that were no different from those induced by saline. After microinjection of 10 pmol of Ang-(1–7) into the nTS of normotensive rats, there was a significant increase in baroreflex sensitivity. In SHR, only the microinjection of a higher dose (25 pmol) of Ang-(1–7) produced a significant increase in baroreflex sensitivity. A significant reduction inbaroreflex sensitivity was observed after microinjection of A-779 (50 pmol) in both strains.ConclusionsThese results indicate that Ang-(1–7) exerts a tonic modulatory effect on the baroreflex control of heart rate at the nTS, probably through a non-AT1non-AT2receptor subtype. In addition, our data showed a reduced sensitivity to Ang-(1–7) at the nTS of SHR, that could be accounting, at least in part, for the decreased baroreflex sensitivity present in this model of hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveCorticotrophin (ACTH)-induced hypertension in the rat is prevented by L- but not D-arginine. We examined the effects of exogenous corticosterone in the male Sprague Dawley (SD) rat to determine whether ACTH- induced hypertension is mediated by corticosterone.MethodsExogenous corticosterone (10, 20 or 40 mg/kg per day) or sham (polyethylene glycol (PEG) 1 ml/kg per day) was injected subcutaneously in divided doses (s/c b.d.) over 15 treatment days to 40 SD rats (n= 10 each group). Subsequently, the effects of L-arginine, D-arginine or L-arginine + N-nitro-L-arginine (NOLA) on corticosterone-induced hypertension (corticosterone 20 mg/kg per day) were examined. Systolic blood pressure (SBP) and metabolic parameters were measured every two days.ResultsTwenty and 40 mg/kg per day of corticosterone increased SBP compared with sham (P< 0.01,P< 0.05 respectively, sham versus respective group). Forty mg/kg per day of corticosterone raised serum corticosterone concentration compared with sham (502 ± 20 versus 364 ± 25 ng/ml,P< 0.001). L-arginine prevented the rise in SBP produced by orticosterone (131 ± 3 to 131 ± 2 mmHg, control versus day 10) but D-arginine did not (129 ± 3 to 142 ± 4 mmHg on day 8,P< 0.01). NOLA blocked the effect of L-arginine and amplified the rise in blood pressure produced by corticosterone (130 ± 3 to 171 ± 6 mmHg on day 10,P< 0.001).ConclusionsThe haemodynamic features of ACTH-induced hypertension were reproduced by corticosterone excess, at concentrations of corticosterone similar to those in studies of exogenous ACTH administration. It is likely that ACTH-stimulated adrenal production of corticosterone accounts for the features of ACTH-induced hypertension in the rat.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID