摘要:

ObjectiveThis study examined the frequency of the Lys198Asn polymorphism in the endothelin-1 (ET-1) gene in women with pre-eclampsia and normal pregnancy; and its contribution to levels of plasma ET-1 and blood pressure.Design and methodsThis was a retrospective study examining the frequency of the ET-1 Lys198Asn polymorphism in 72 proteinuric pre-eclamptics and 81 normal pregnant women. Height, weight, blood pressure and plasma ET-1 were measured antenatally and at 6 weeks post-partum. Using specific mutagenic primers, the frequency of the G/G (normal), G/T heterozygote and T/T (mutant) genotypes of the Lys198Asn polymorphism were examined.ResultsThe polymorphism was not associated with pre-eclampsia. However, in the combined pregnant groups after correction for BMI and group, a significant effect of the T-allele (T/T,G/T) on systolic blood pressure was found (121 ± 1.5 mmHg compared with 116 ± 1.3 mmHg in the G/G homozygotes). A significant interaction was found between the T-allele and pregnancy in determining systolic blood pressure, so that the effect was no longer seen post-partum. Pregnant women with the T/T genotype had significantly elevated plasma ET-1 levels 5.8 pg/ml [confidence interval (CI) 3.7–9.1] compared with 3.1 pg/ml (CI 2.6–3.8) in the G/T heterozygotes and 3.6 pg/ml (CI 3.0–4.1) in the normal G/G homozygotes.ConclusionThe Lys198Asn polymorphism does not directly contribute to the incidence of pre-eclampsia. However, the association of the T-allele with raised blood pressure and the T/T genotype with increased plasma ET-1 levels suggest that this polymorphism may interact with other genes or environmental factors to sensitize pregnant women to develop pre-eclampsia.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo determine whether polymorphisms in the renin–angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol.Design and methodsEighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the β1adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction.ResultsThe mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (−18±11 SD versus−7±10 mmHg,P= 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P= 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment.ConclusionsACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo determine the roles of endothelin (ET)-receptor subtypes in the effects of exogenous and endogenous ETs on regional kidney blood flow in anaesthetized rabbits.Design and methodsThe effects on regional kidney blood flow of the ETAantagonist BQ610, and the ETBantagonist BQ788, were tested. We also examined the effects of intravenous and renal arterial bolus doses of ET-1, and how these responses are modified by pretreatment with BQ610 and BQ788.ResultsBQ610 reduced mean arterial pressure (MAP, 3%), and increased total renal blood flow (RBF, 10%), cortical perfusion (CBF, 11%) and medullary perfusion (MBF, 16%). BQ788 increased MAP (6%) and reduced RBF (16%) and CBF (13%) but not MBF. The effects of BQ788 were abolished by pretreatment with BQ610. Intravenous ET-1 (300 ng/kg) reduced RBF and CBF, but increased MBF. BQ788 potentiated ET-1 mediated reductions in CBF, and abolished increases in MBF. BQ610 blunted reductions in RBF and CBF produced by ET-1, but did not significantly affect MBF responses. The renal vascular effects of intravenous ET-1 were mimicked by lower doses (1–30 ng/kg) administered into the renal artery.ConclusionsEndogenous ETs act at ETA-receptors to reduce MBF and CBF, but ETB-receptors have little direct role in physiological control of renal haemodynamics. Bolus doses of ET-1 act at ETB-receptors in the kidney to increase MBF. The effects of bolus ET-1 on the cortical vasculature appear to result from the competing influences of ETA-mediated vasoconstriction and ETB-mediated vasodilatation.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Objective:This study was designed to evaluate the capacity of norepinephrine (NE) to induce hypertrophic remodeling of small arteries in rats, and to determine the involvement of endothelin (ET) to initiate and maintain it.Design and results:Treatment with NE (2.5μg/kg per min) for 14 or 28 days produced a similar inward hypertrophic remodeling, characterized by a smaller lumen, but increased media thickness and cross-sectional area. Arterial stiffness was reduced. Histological evaluation confirmed the hypertrophic nature of remodeling. Concomitant administration of LU135252 (ET-receptor antagonist) for the first 14 days of NE administration prevented the development of hypertrophy, without altering arterial mechanics. Treatment with the same antagonist from day 14 to day 28 of NE or angiotensin II (Ang II) treatment failed to regress established vascular hypertrophy. In contrast, normalization of arterial structure was observed with prazosin, anα-adrenergic blocker. Endothelin content in small mesenteric arteries showed a transient elevation following chronic NE administration.Conclusions:Increased circulating NE levels are associated with hypertrophic remodeling of small arteries, in which ET plays an initiating role. However, the maintenance of vascular hypertrophy is ET-independent, either in the presence of augmented circulating levels of NE or Ang II. Thus, early rather than late treatment with ET-receptor antagonists may be a preferable approach to limit small artery-mediated end-organ damage in cardiovascular diseases.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo investigate if antihypertensive treatment could improve endothelium-dependent vasodilatation in hypertensive patients, and whether the angiotensin II subtype-1 (AT1)-receptor antagonist irbesartan and the β1-receptor antagonist atenolol would differ in this respect.Subjects and methodsThirty-four patients (28 men and six women) with mild-to-moderate essential hypertension (diastolic blood pressure 90–120 mmHg) were randomized to once daily 150–300 mg irbesartan or 50–100 mg atenolol in a double-blind fashion, preceded by a placebo run-in period. Forearm blood flow (FBF) was assessed by venous occlusion plethysmography during local intra-arterial infusions of methacholine and sodium nitroprusside, to evaluate endothelium-dependent and endothelium-independent vasodilatation, respectively. Measurements of FBF were undertaken at the end of the run-in placebo period and repeated after 3 months of active antihypertensive treatment.ResultsIrbesartan and atenolol induced a similar decline in blood pressure (from 171/107 to 158/98 mmHg,P< 0.05), and improved endothelium-dependent vasodilatation (e.g. an increase in FBF response to 4 μg/min methacholine from 325±29% to 411±41%,P<0.05), with no difference between the two study drugs. No significant changes in endothelium-independent vasodilatation were induced by irbesartan or by atenolol.ConclusionsThe present study shows that 3 months of antihypertensive therapy with irbesartan or atenolol improves endothelium-dependent vasodilatation.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The glutathione (GSH) system plays an important role in reducing oxidative stress, the increase of which has been linked to the pathogenesis of hypertension. The aims of this study were to investigate: (1) whether the GSH system was impaired in aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHR), and (2) whether this system could be up-regulated by the phase-2 enzyme inducers, sulforaphane andt-butylhydroquinone (t-BHQ). Basal levels of cellular GSH, GSH-reductase and GSH-peroxidase were significantly lower in SMCs from SHR than from normotensive Wistar–Kyoto (WKY) rats. Heme oxygenase-1 (HO-1) was significantly higher in SHR SMCs, which correlated with the higher oxidative stress experienced by these cells. No differences were observed in the basal activity of GSH-S-transferase nor in the ability to synthesize GSH between SMCs from these two strains. Sulforaphane (0.05–1 μmol/l) andt-BHQ (10–100 μmol/l) induced significant and concentration-dependent increases in cellular GSH levels, HO-1 protein content and activities of GSH-reductase and GSH-peroxidase in SMCs from both rat strains. Upregulation of phase 2 enzymes correlated with a decrease in oxidative stress experienced by the SMCs, particularly with SHR. We conclude that SHR SMCs experience greater oxidative stress than WKY SMCs and that malfunction of the GSH system contributes to the enhanced oxidative stress in SHR SMCs.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesIt has been shown that a diminished sympathetic activity contributes to the hypotensive and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors (ACEI). Besides an inhibition of central sympathetic tone and peripheral noradrenaline release, we hypothesized that the interactions of ACEI with the sympathetic system may include a modulation of neuronal catecholamine uptake by peripheral nerves.DesignWe investigated the influence of fosinopril on noradrenergic uptake into cardiac neuronesin vitroandin vivoin acute and chronic models.Methods and resultsAcute administration of fosinoprilat to isolated perfused rat hearts increased the extraction of [3H]-noradrenaline from the perfusate by 39%. Treatment (14 days) of spontaneously hypertensive rats (SHR) with fosinopril (20 mg/kg per day) enhanced the cardiac uptake of i.v. administered [3H]-noradrenaline by 28%. The endogenous left ventricular content of noradrenaline was increased by 49% after an antihypertensive treatment of SHR with fosinopril (20 mg/kg per day). Identical increases in cardiac noradrenaline stores (53%) were observed in SHR treated with a blood pressure ineffective dose of fosinopril (0.2 mg/kg per day). The myocardial content of adrenaline was increased in parallel to noradrenaline after both dose regimes.ConclusionsIt is concluded that ACEI increases neuronal uptake of catecholamines in SHR in a blood pressure-independent manner. This effect occurs acutely and is independent of central sympathetic activity. Therefore, we hypothesize that ACEI modulate the activity of the cardiac noradrenaline transporter by direct activation. The improved uptake of noradrenaline may contribute to the antihypertensive and cardioprotective effects of ACEI.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Objective and designAngiotensin converting enzyme inhibitors are reported to inhibit the collagen accumulation involved in left ventricular hypertrophy. We tested the effect of captopril and enalapril on the conversion of procollagen to collagen in short-term tissue cultures in order to study the possible mechanisms by which the antifibrotic effect of this group of inhibitors takes place.MethodsWe employed short-term cartilage and tendon tissue cultures to monitor the conversion of procollagen to collagen. After pulse-labelling with [14C]-proline, the cultures were incubated further with the test compounds in different concentrations for a 180 min chase period. The reaction was stopped and radioactive collagenous peptides were analysed by gel electrophoresis. The amounts of collagenous proα and α chains were estimated, and the inhibition of procollagen to collagen conversion was calculated relative to 0 min control (100% inhibition) and 180 min control (0% inhibition) samples.ResultsInhibition (50%) was obtained with 7 mmol/l captopril and 22 mmol/l enalapril in the cartilage cultures. Both compounds seemed to inhibit the conversion in clearly lower concentrations in tendon cultures, 4 mmol/l and 7 mmol/l, respectively, were sufficient for 50% inhibition. Angiotensin I, II, saralasin and bradykinin did not have any effect on conversion at 3.5, 9, 2 and 4 mmol/l concentrations, respectively.ConclusionThe peptidase inhibitors captopril and enalapril are able to inhibit the conversion of procollagen to collagen, which is a proteolytic process, possibly by inhibiting the specific procollagen proteases. Whether this phenomenon is involved in the antifibrotic property of angiotensin converting enzyme inhibitors warrants further study, as does the question of whether new antifibrotic agents could be developed on this basis.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo define the role of the type 1 angiotensin II (AT1) and type II (AT2) receptors in the development of salt-sensitive hypertension induced by sensory nerve degeneration.Design and methodsNeonatal Wistar rats were given capsaicin 50 mg/kg s.c. on the first and second days of life. After weaning, male rats were divided into six groups and treated for 3 weeks with: control + high sodium diet (4%, CON-HS), capsaicin pretreatment + normal sodium diet (0.5%, CAP-NS), CAP-HS, CAP + HS + candesartan (10 mg/kg per day) (CAP-HS-CAN), CAP + HS + PD 123319 (30 mg/kg per day) (CAP-HS-PD), and capsaicin pretreatment + high sodium diet + candesartan + PD 123319 (CAP-HS-CAN-PD). Mean arterial pressure (MAP) was measured by carotid arterial catheterization. Urinary Na+concentrations were determined by using a flame atomic absorption spectrophotometer. Levels of calcitonin gene-related peptide (CGRP) in dorsal root ganglia (DRG) and plasma renin activity (PRA) were determined by radioimmunoassay.ResultsCGRP contents in DRG were decreased by capsaicin (P<0.05). MAP was higher in CAP-HS rats compared with all the other groups (P<0.05). The 24 h urine and sodium excretion increased when a high salt diet was given, but they were lower in CAP-HS and CAP-HS-CAN than in CON-HS (P<0.05). PRA was suppressed in CON-HS and CAP-HS compared with CAP-NS, but it was higher in CAP-HS than in CON-HS (P<0.05).ConclusionInsufficiently suppressed PRA by high salt intake may contribute to increased salt sensitivity and account for effectiveness of candesartan in lowering blood pressure in this model. Furthermore, PD 123319 attenuates the development of hypertension in salt-loaded rats neonatally treated with capsaicin, indicating that the AT2 receptor contributes to the increase in blood pressure.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveThe expression of α1-adrenergic receptor subtypes in peripheral blood lymphocytes was investigated in 28 essential hypertensive patients as well as in the peripheral blood lymphocytes and aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto (WKY) rats.Methodsα1-Adrenergic receptors were quantified by radioligand binding assays, employing [3H]-prazosin as the radioligand in association with compounds displaying different degrees of selectivity for α1A-, α1B- and α1D-adrenergic receptor subtypes.ResultsThe affinity of [3H]-prazosin binding was similar in peripheral blood lymphocytes of different stage essential hypertensive and normotensive subjects or of SHR and age-matched normotensive WKY rats as well as in the aortas of SHR and WKY rats. The radioligand binding assay revealed no change in the expression of α1-adrenergic receptors in peripheral blood lymphocytes of essential hypertensives compared with normotensive subjects; a moderate decrease of α1B-adrenergic receptors and an increase of α1D-adrenergic receptors. The relative densities of the α1-adrenergic receptor subtypes were similar in the three groups of essential hypertensives. In peripheral blood lymphocytes and in aorta of SHR, [3H]-prazosin binding was significantly reduced compared with normotensive WKY rats. The expression of α1-adrenergic receptor subtypes in peripheral blood lymphocytes of SHR was similar to that found in peripheral blood lymphocytes of essential hypertensives.ConclusionsChanges of lymphocyte α1-adrenergic receptor subtypes in essential hypertensives are similar to those observed in lymphocytes and vascular tissues of animal models of hypertension. This suggests that assays of lymphocyte α1-adrenergic receptors may represent an indirect marker of their involvement in essential hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2001

数据来源: OVID