摘要:

ObjectiveCoupling factor 6 is an endogenous inhibitor of prostacyclin synthesis and might function as an endogenous vasoconstrictor in the fashion of a circulating hormone in rats. We investigated the role of coupling factor 6 in human hypertension.Methods and resultsThe patients with essential hypertension (EH) (n= 30) received a series of normal salt diet (12 g salt/day) for 3 days, low salt diet (2 g salt/day) for 7 days, and high salt diet (20–23 g salt/day) for 7 days. Normotensive control subjects (n= 27) received normal and low salt diets. The plasma level of coupling factor 6, measured by radioimmunoassay, during normal salt diet was higher in patients with EH than in normotensive subjects (17.6 ± 1.7 versus 12.8 ± 0.5 ng/ml,P<0.01). Whereas the plasma level of coupling factor 6 was unchanged after salt restriction in normotensive subjects, it was decreased after salt restriction (from 12 g/day to 2 g/day) and was increased after salt loading (from 2 g/day to 20–23 g/day) in patients with EH. This increase in plasma level of coupling factor 6 was abolished by oral administration of ascorbic acid, but the level of blood pressure was unaffected. The percentage changes in plasma coupling factor 6 level after salt restriction and loading were positively correlated with those in mean blood pressure (r= 0.57,P<0.01), and negatively correlated with those in plasma nitric oxide level (r= –0.51,P<0.05).ConclusionThese indicate that circulating coupling factor 6 is elevated in human hypertension and modulated by salt intake presumably via reactive oxygen species.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveIntracellular glutathione in its reduced state is a principal cellular biomolecule with antioxidant activity. Glutathione and homocysteine metabolism are closely associated. As both oxidative stress and hyperhomocystinemia are associated with hypertension, we assessed the relationships between these variables.Design and settingAn observation-based case–control study, performed at a university teaching hospitalPatientsMiddle-aged male patients with untreated uncomplicated essential hypertension (mean ± standard deviation age 53.0 ± 7.2 years,n= 48) before any treatment and controls with similar age distributions (age 51.6 ± 5.5 years,n= 28) were evaluated.MethodsIn all subjects, the plasma levels of homocysteine, lipids, creatinine, protein, and glucose were measured. Reduced and oxidized glutathione and folic acid were measured from red blood cells (RBC).ResultsThe hypertensive patients had decreased levels of red blood cell reduced glutathione (RBC-GSH) and increased levels of oxidized glutathione, which resulted in elevated ratio of oxidized/reduced glutathione as compared to controls (P<0.001). Plasma homocysteine levels were significantly higher in the hypertensive patients versus the age-matched controls (P<0.004). In the hypertensive patients, RBC-GSH correlated inversely with systolic blood pressure, serum creatinine, protein and RBC folic acid. No correlation was detected between RBC-GSH and homocysteine. In the controls, RBC-GSH correlated inversely with homocysteine, RBC folic acid and creatinine. According to multiple regression, in the hypertensive patients RBC-GSH was related to systolic blood pressure, hemoglobin, plasma homocysteine, creatinine and protein. Such a relationship was not detected for the controls.ConclusionIn untreated hypertensive patients both homocysteine and systolic blood pressure are associated with intracellular oxidative stress as determined by RBC-GSH.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo investigate whether superoxide mediates angiotensin (Ang) II-induced vasoconstriction.MethodsHuman coronary arteries (HCAs), porcine femoral arteries (PFA) and porcine coronary arteries (PCAs) were mounted in organ baths and concentration–response curves to Ang II, the nitric oxide (NO) donorS-nitroso-N-acetylpenicillamine (SNAP) and the NAD(P)H oxidase substrate NADH were constructed in the absence and presence of superoxide inhibiting and activating drugs. Extracellular superoxide was measured using cytochrome c reduction.ResultsAng II constricted both HCAs and PFAs. In HCAs, the NAD(P)H inhibitors diphenyleneiodonium (DPI) and apocynin, and the xanthine oxidase (XO) inhibitor allopurinol, but not the superoxide dismutase (SOD) mimetic tempol or the SOD inhibitor diethyldithiocarbamate (DETCA), reduced this constriction. Catalase potentiated Ang II in HCAs, indicating a vasodilator role for H2O2. DPI, tempol and SOD did not affect Ang II in PFAs. DPI, apocynin and allopurinol relaxed preconstricted HCAs. Although the relaxant effects of the NO donor SNAP in PCAs was reduced by DETCA, indicating that superoxide-induced constrictions depend on NO inactivation, the apocynin-induced relaxations were NO independent. Moreover, NADH relaxed all vessels, and this effect was blocked by KCl but not DPI or NO removal. Xanthine plus XO also relaxed HCAs and PCAs. Incubation of human or porcine arteries with Ang II or NADH did not result in detectable increases of extracellular superoxide within 1 h.ConclusionsAcute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

BackgroundVascular structural alterations in small resistance arteries of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. In fact, no difference in the smooth muscle cell volume (CV) between normotensive subjects (NT) and essential hypertensive patients was observed. However, experimental models of hypertension with chronic infusion of agonists of adrenergic receptors were characterized by the presence of smooth muscle cell hypertrophy or hyperplasia. Recently, we have observed the presence of vascular smooth muscle cell hypertrophy in patients with renovascular hypertension.ObjectiveThe aim of the study to investigate the structural characteristics of subcutaneous small resistance arteries of NT, of EH, and of patients with phaeochromocytoma (Phaeo).Patients and methodsThirty Phaeo, 30 NT and 30 EH were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small resistance arteries (relaxed diameter 160–280 μm) were dissected and mounted on a micromyograph and the media : lumen ratio was calculated. In nine Phaeo, nine NT and 13 EH the cell volume was measured by an unbiased stereological principle, the ‘disector’ method.ResultsNo difference in smooth muscle cell volume was observed between groups. However, inward remodeling in Phaeo was less marked than in EH, although the increase in media : lumen ratio was similar compared with NT. However, the lack of changes in media cross-sectional area, compared with NT, suggest that there has been little hypertrophy, the changes observed thus being eutrophic.ConclusionsOur data show, based on a reasonably large sample, that a pronounced activation of the adrenergic system is not associated with vascular smooth muscle cell hypertrophy or hyperplasia in humans. It is therefore possible that adrenergic mechanisms may have a relevant role in the development of eutrophic remodeling in small vessels.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives and designAngiotensin II (Ang II)-induced renal damage is associated with perivascular inflammation and increased oxidative stress. We tested the hypothesis whether entacapone, a catechol-O-methyltransferase (COMT) inhibitor exerting antioxidative and anti-inflammatory properties, protects against the Ang II-induced inflammatory response and end-organ damage.MethodsSamples from double-transgenic rats harbouring human renin and human angiotensinogen genes (dTGR) and normotensive Sprague–Dawley rats (SD) were assessed by light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and high pressure liquid chromatography. The effects of entacapone treatment for 3 weeks were examined in dTGR and SD.ResultsEntacapone completely prevented cardiovascular mortality and decreased albuminuria by 85% in dTGR. Entacapone ameliorated Ang II-induced vascular and glomerular damage, leucocyte infiltration, and intercellular adhesion molecule-1 (ICAM-1) overexpression in the kidneys. Serum 8-isoprostane concentration, as well as renal nitrotyrosine and 8-hydroxydeoxyguanosine expressions, all markers of oxidative stress, were markedly increased in dTGR and normalized by entacapone. Entacapone also decreased p22phox mRNA expression in the kidney. COMT expression was increased by 500% locally in the renal vascular wall in dTGR; however, COMT activity in the whole kidney remained unchanged. Urinary dopamine excretion, a marker of renal dopaminergic tone, was decreased by 50% in untreated dTGR. Even though entacapone decreased renal COMT activity by 40%, the renal dopaminergic tone remained unchanged in entacapone-treated dTGR.ConclusionOur findings suggest that entacapone provides protection against Ang II-induced renal damage through antioxidative and anti-inflammatory mechanisms, rather than by COMT inhibition-induced changes in renal dopaminergic tone.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

BackgroundPrevious studies have indicated that catechol-O-methyltransferase (COMT) can modulate renal dopaminergic tone.ObjectiveTo test the hypothesis that COMT blockade protects from salt-induced hypertension.MethodsCOMTgene-disrupted (−/−) mice and wild-type controls received a high-sodium diet (NaCl 6%) for 3 weeks. Blood pressure and heart rate were recorded by radiotelemetry. Tissue and urine samples were assessed by light microscopy and high-performance liquid chromatography. The effects of nitecapone treatment were also examined. Systolic blood pressure and heart rate during normal sodium diet were similar inCOMT(−/−) and wild-type mice. The high-sodium diet increased night-time systolic and diastolic blood pressures in wild-type mice, whereas blood pressure inCOMT(−/−) mice remained unaltered. In wild-type mice, the sodium-induced increase in blood pressure was completely normalized by treatment with the COMT inhibitor, nitecapone. At baseline, 24-h urinary excretion of levodopa (l-DOPA), dopamine and noradrenaline was increased by 145, 85 and 74%, respectively, inCOMT(−/−) mice compared with wild-type controls. InCOMT(−/−) and wild-type mice, a high-sodium diet increased urinary l-DOPA excretion by 405 and 660% (reflected as 102 and 212% increases in dopamine excretion), respectively. The absolute amounts of urinary l-DOPA and dopamine remained 60 and 20% greater inCOMT(−/−) mice. The high-sodium diet did not influence renal cortical COMT activity.ConclusionOur findings suggest that COMT deficiency in mice increases the availability of l-DOPA, leading to enhanced dopaminergic tone, which may be associated with resistance to salt-induced hypertension. The findings of the present study also underline the importance of COMT in the regulation of blood pressure, sodium excretion and renal dopaminergic tone.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectivesTo study the cellular distribution and the expression of the major isoforms of NO synthase (NOS) and of nitrotyrosine in the kidney in spontaneous hypertension.Design and methodsWe have studied by immunohistochemistry the location of the endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) isoforms and nitrotyrosine in kidney slices from normotensive Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) using specific antibodies. In order to quantify the expression of these proteins, we have analyzed dissected renal cortical and medullary sections by means of Western blot.ResultsTubular cells were immunoreactive to nNOS and more numerous in the renal medulla of the SHR compared with that of the WKY, specifically in the outer medulla and the papillary region. Western blot also showed higher expression of nNOS in the renal medulla, but not the renal cortex of the SHR. In contrast, iNOS and eNOS distribution and expression were similar in the kidneys of WKY rats and SHR. Immunohistochemistry showed immunoreactive cells to nitrotyrosine in a variety of renal cells similarly distributed in SHR and WKY kidneys. Western analysis detected three proteins of 14.5, 23.7 and 39 kDa immunoreactive to nitrotyrosine, showing a higher expression in the renal cortex compared to the renal medulla.ConclusionsThe expression of nNOS is higher in the renal medulla of the SHR, and the distribution of eNOS, iNOS and nitrotyrosine is similar in SHR and WKY rats. It is proposed that the higher expression of the neuronal isoform in the medullary tubular cells is a protective mechanism aimed to improve renal function in spontaneous hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveSecondary activation of the renin–angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2).DesignRen2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague–Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1).ResultsDuring the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P< 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P<0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P<0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P<0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2.ConclusionET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveThis study examined the separate and combined effects of hypertension and diabetes on renal cortical expression of protein kinase C (PKC) isoforms -β1, -β2, -α and -&epsis;, to determine whether albuminuria is the result of an increase in the expression of one or a combination of PKC isoforms. Corresponding changes in renal microtubules were also assessed.MethodsDiabetes (D) was induced in Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) by streptozotocin. After 24 weeks, PKC expression was determined by Western blot and microtubules were assessed by immunohistochemistry for α-tubulin protein.ResultsDiabetes was characterized by significant increases in glycated haemoglobin (HbA1c) as compared to controls (C). There was a significant increase of three- to four-fold in PKC protein content for all four isoforms in renal cortex from SHR-C and WKY-D, and similar and significant levels of albuminuria (∼10 mg/24 h) observed in these groups in comparison to WKY-C (∼1 mg/24 h). Interestingly, PKC-α and -&epsis; but not PKC-β1and -β2protein content was doubled in SHR-D, and albuminuria increased tenfold (∼100 mg/24 h) in comparison to SHR-C and WKY-D. These changes were paralleled by a significant decrease in α-tubulin protein content of ∼50% in SHR-C and ∼33% in WKY-D compared to WKY-C, with a further decrease of ∼67% in SHR-D compared to WKY-C.ConclusionThese findings indicate that PKC expression can be increased by either diabetes or hypertension, and that there are further specific increases in the expression of PKC isoforms -α and -&epsis; in the model of combined diabetes and hypertension. In addition, the degree of disruption in microtubular cytoskeleton appears to be correlated with PKC activation and levels of albuminuria.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

BackgroundThe risks and benefits of treating hypertension in individuals older than 80 years are uncertain. A meta-analysis has suggested that a reduction in stroke events of 36% may have to be balanced against a 14% increase in total mortality.ObjectivesTo report the results of the pilot study of the Hypertension in the Very Elderly Trial (HYVET), which is in progress to address these issues.MethodsThe HYVET-Pilot was a multicentre international open pilot trial. In 10 European countries, 1283 patients older than 80 years and with a sustained blood pressure of 160–219/90–109 mmHg were allocated randomly to one of three treatments: a diuretic-based regimen (usually bendroflumethiazide;n= 426), an angiotensin-converting enzyme inhibitor regimen (usually lisinopril;n= 431) or no treatment (n= 426). The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment. Target blood pressure was<150/80 mmHg and mean follow-up was 13 months.ResultsIn the combined actively treated groups, the reduction in stroke events relative hazard rate (RHR) was 0.47 [95% confidence interval (CI) 0.24 to 0.93] and the reduction in stroke mortality RHR was 0.57 (95% CI 0.25 to 1.32). However, the estimate of total mortality supported the possibility of excess deaths with active treatment (RHR 1.23, 95% CI 0.75 to 2.01).ConclusionsThe preliminary results support the need for the continuing main HYVET trial. It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 (nine non-fatal), but may be associated with 20 extra non-stroke deaths.

ISSN:0263-6352    

出版商:OVID    

年代:2003

数据来源: OVID