摘要:

ObjectivesTo investigate the role of transforming growth factor-β1 (TGF-β1) on Ca2+-dependent mechanisms elicited by angiotensin II in aortic vascular smooth muscle cells (VSMC) of Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).MethodsCai2+release induced by angiotensin II (1 μmol/l) was studied in cultured VSMC isolated from the aortas of 6-week-old WKY rats and SHR. Intracellular Ca2+(Cai2+) was assessed in Fura-2 loaded cells using fluorescent imaging microscopy. Angiotensin II receptors were analysed by binding studies.ResultsPretreatment of VSMC for 24 h with TGF-β1 significantly increased angiotensin II-induced Cai2+mobilization from internal stores in SHR, while Ca2+influx was not altered. This effect involves tyrosine kinase and is not due to an increase in angiotensin II binding sites, or a change in the affinity of the receptors. By contrast, TGF-β1 did not modify the response of VSMC from WKY rats to angiotensin II.ConclusionsThese results help our understanding of the interactions between the pathways activated by TGF-β1 and the G protein-coupled receptor signalling pathway, and their role in genetic hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveStudies in normal humans and in patients with type 2 diabetes mellitus have demonstrated a close inverse relationship between peripheral insulin sensitivity and the frequency of short-term insulin secretory pulses in the systemic circulation. Our objective was to study this relationship in essential hypertension.DesignStudy of insulin sensitivity and insulin pulse characteristics in hypertensive subjects and normotensive controls using well-established techniques.MethodsTwelve subjects with essential hypertension and 12 age-and sex-matched normotensive controls were recruited. Insulin action was measured using the glucose clamp technique combined with isotope dilution methodology. Insulin pulsatility in the peripheral circulation was assessed by sampling every 2 min for 90 min after an overnight fast. Pulses were identified using the computer program Pulsar.ResultsInsulin sensitivity index (glucose infusion rate/serum insulin) was lower in the hypertensive patients (P= 0.01) and fasting insulin was increased (P= 0.008) compared to controls. The frequency and amplitude of insulin pulses were similar in the two groups. Insulin pulse frequency and insulin sensitivity were inversely related in the normotensive group (r= −0.68,P= 0.015), but not in the hypertensive group (r= −0.23,P= 0.48). Insulin clearance was reduced in the hypertensive group (P= 0.03), and was inversely related to insulin pulse frequency in the two groups combined (r= 20.51, P = 0.01).ConclusionsInsulin action was not related to insulin pulse frequency in essential hypertension, in contrast to the situation in normal man.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveThe major advantage of dual inhibitors of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) is their ability to lower blood pressure irrespective of renin or volume status. The aim of this study was to determine whether dual NEP/ACE inhibition produces different effects on cardiovascular structure and fibrosis, hormonal parameters and inhibition of tissue enzymes compared with selective inhibition of ACE and NEP in the spontaneously hypertensive rat (SHR).MethodsMale SHRs received the dual NEP/ACE inhibitor (S21402, 100 mg/kg per day), the ACE inhibitor (captopril, 50 mg/kg per day), the NEP inhibitor (SCH42495, 60 mg/kg per day) or vehicle for 2 weeks.ResultsS21402 produced equivalent blood pressure lowering effects to captopril (vehicle, 220 ± 1 mmHg; S21402, 189 ± 2 mmHg; captopril, 187 ± 3 mmHg), but was a more effective antihypertensive agent than SCH42495 (214 ± 2 mmHg,P<0.01). All treatments reduced left ventricular mass (P<0.05) and cardiac fibrosis (P<0.01). S21402 inhibited renal NEP and ACE (P<0.01), SCH42495 inhibited renal NEP (P<0.01), and captopril inhibited renal ACE (P<0.01). Captopril and S21402 increased plasma renin activity (P<0.05), but the rise with S21402 was attenuated compared with that caused by captopril (P<0.01). All treatments reduced plasma aldosterone levels (P<0.01), and NEP inhibition with SCH42495 and S21402 increased plasma atrial natriuretic peptide (ANP;P<0.05).ConclusionsThese results indicate that selective NEP inhibition has major benefits in the regression of cardiac hypertrophy and reduction of fibrosis but has limited antihypertensive effects. The dual NEP/ACE inhibitor S21402 offered no advantage over the selective ACE inhibitor in terms of blood pressure reduction, or attenuation of cardiac hypertrophy and fibrosis, but did increase plasma ANP and blunted the reactive rise in renin with ACE inhibition. Further studies are needed to determine whether more complete blockade of the renin-angiotensin system with dual NEP/ACE inhibition results in additional benefits in terms of morbidity and mortality in cardiovascular disease.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundHypertensive left ventricular (LV) hypertrophy has been associated with diastolic dysfunction. However, the underlying physiological relationship between LV size and diastolic function remains to be clarified. The aim of this study was to evaluate the relationship between several measures of diastolic filling and LV mass in a population sample.MethodsWe used M-mode and Doppler echocardiography to compare left ventricular mass index (LVMI) and wall thickness with five measures of ventricular diastolic filling (ratio of the peak early mitral inflow velocity to the peak atrial mitral inflow velocity, deceleration time of early mitral inflow, isovolumetric relaxation time, ratio of the peak pulmonary venous systolic to diastolic flow and difference between the durations of the pulmonary venous and mitral inflow atrial waves) in 159 healthy volunteers.ResultsLVMI was significantly (P<0.0001) greater in men (81.3 g/m2, interquartile range: 67–94) than women (59.7 g/m2, interquartile range: 49–74), but no gender differences were observed in diastolic filling. Higher age, blood pressure and heart rate showed significant correlation with diminished diastolic filling. However, no measure of diastolic filling correlated with LVMI or wall thickness in either univariate or multiple regression analyses that adjusted for relevant covariates.ConclusionsLVMI does not explain physiological differences in diastolic filling. The significant decline in diastolic filling with age reflects changes in the quality rather than the quantity of myocardial tissue.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundMarkers of electrical instability of the ventricular myocardium, namely abnormal repolarization and late potentials, are frequently observed in patients with hypertension when both ventricular arrhythmias and left ventricular hypertrophy are present. This information cannot be extrapolated to the population of hypertensive patients with ventricular arrhythmias but without left ventricular hypertrophy.ObjectiveTo evaluate QT duration, QT dispersion and the incidence of ventricular late potentials in patients with essential hypertension, already on anti-hypertensive therapy, both with and without non-sustained ventricular arrhythmia.DesignThe study population consisted of 49 patients with essential hypertension who were compared to 89 control normotensive subjects both with and without frequent (> 30 per h) ventricular ectopic beats (VPBs). Patients were divided into four groups: (1) hypertensive patients without VPBs (H,n= 19), (2) hypertensive patients with VPBs (HA,n= 30), (3) normotensive subjects without VPBs (C,n= 28), and (4) normotensive subjects with VPBs (CA,n= 61).MethodsEchocardiographic parameters, QT interval, QT dispersion and signal-averaged ECG were evaluated without withdrawing anti-hypertensive drugs.ResultsIn no case was left ventricular hypertrophy documented. The number of VPBs during 24 h Holter recording (median 11 343 versus 7617) and the incidence of repetitive VPBs (37 versus 46% of patients) were similar in the two groups of patients (HA versus CA). Signal-averaged ECG parameters were normal and not different between the four groups. QT interval was longer in hypertensive patients compared to controls irrespective of the presence of VPBs. QT dispersion was slightly greater in subjects with VPBs, both hypertensive and normotensive, compared to subjects without arrhythmias.ConclusionsIn patients with hypertension well-controlled by drug therapy and without left ventricular hypertrophy, frequent VPBs are not associated with markers indicating an electrophysiological substrate for re-entrant arrhythmias. However, QT prolongation suggests the persistence of a higher risk of cardiovascular mortality that is independent of the presence of VPBs.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveIn this study, we tested the hypothesis that sympathetic over-activity may cause metabolic abnormalities and affect left ventricular (LV) structure and mass early in life.Subjects and settingThe study population consisted of 111 healthy adolescents and young adults living in Tecumseh, Michigan (USA).Main outcome measuresCorrelations of LV mass and structure with several clinical variables in relation to the activity of the sympathetic nervous system.MethodsPower spectrum density estimates of heart rate variability were calculated with an auto-regressive method, and subjects were divided by cluster analysis into two groups according to low-frequency and high-frequency components. LV data were obtained by echocardiographic assessment.ResultsSubjects with signs of sympathetic over-activity (n= 38, group 1) had higher heart rate, blood pressure (BP), waist/hip ratio and cholesterol levels than the rest of the group (n= 73, group 2). In group 1 subjects, insulin emerged as the strongest univariate correlate of interventricular septum and posterior wall thicknesses (P<0.001 for both) and of LV mass (P= 0.009). These relationships remained significant when body mass index was accounted for. By contrast, the marginal univariate relationship with diastolic BP did not remain significant in multivariate analysis. In group 2 subjects, BP was strongly correlated with LV wall thickness and mass both in univariate (Pvalues from 0.03 to <0.001) and multivariate analyses, while insulin was not. The interactive effect of sympathetic activity and insulin on echocardiographic data was confirmed by multivariate analyses performed in the subjects grouped together (Pvalues from 0.02 to 0.001 for the sympathetic activity × insulin interaction term).ConclusionsIn young subjects with heightened sympathetic activity and initial metabolic abnormalities, insulin is a strong determinant of LV wall thickness and geometry, while in subjects with normal autonomic nervous system activity, the main determinant of left ventricular size is the haemodynamic load.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveAn inherited reduction in nephron number has been implicated in the development of salt-sensitive hypertension and end stage renal disease. The Munich Wistar Frömter (MWF) rat represents a genetic model with a 30–50% reduction of nephrons compared with normal rats. MWF rats develop spontaneous hypertension and increased urinary albumin excretion (UAE). We addressed the question whether the inherited defect in this model leads to salt-sensitive hypertension.MethodsAt the age of 6 weeks, we started male and female MWF/Fub rats and salt-resistant Lewis (Lew) reference rats on either a normal NaCl (0.2%) or a high NaCl (8%) diet (n= 8, each group). Systolic blood pressure (SBP) and UAE were measured at 14 weeks.ResultsUnder a normal diet, MWF/Fub rats demonstrated significantly elevated SBP compared to Lew rats both in male (165 ± 2 versus 133 ± 3 mmHg,P<0.0001) and female (156 ± 3 versus 134 ± 3 mmHg,P<0.0001) rats. After high NaCl treatment, SBP was significantly higher in both male and female MWF/Fub rats (+55 mmHg and +36 mmHg,P<0.0001, respectively) compared with MWF/Fub under a normal diet. UAE was also significantly higher in male and female MWF/Fub rats after high NaCl excess (P<0.0005, respectively). In contrast, both SBP and UAE remained unchanged in response to high NaCl in Lew rats.ConclusionsOur findings demonstrate that both the hypertension and UAE are sensitive to high NaCl loading in female and male MWF/Fub rats. Thus, an inborn nephron deficit may lead to salt-sensitive hypertension and renal dysfunction.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveA dietary combination of high salt and low potassium (HS-LK) exacerbates hypertension in Dahl salt-sensitive (DS) rats and renders Dahl salt-resistant (DR) rats hypertensive. In both strains, the hypertension is accompanied by remodelling of the renal resistance vasculature, and is attenuated by peripheral chemical sympathectomy. In the current study, we sought to determine whether the sympathetic nervous system is causally involved in mediating the renal vascular and haemodynamic alterations associated with HS-LK feeding in Dahl rats.DesignTwo groups each of DS and DR rats were maintained on HS-LK diet (8% NaCl, 0.2% KCl) for 8 weeks. One group of DS (n= 9) and DR (n= 8) were treated with 6-hydroxydopamine (6-OHDA) in 0.001 N HCl vehicle to chemically ablate peripheral sympathetic nerve terminals. The two remaining groups (n= 8 each) received equivalent injections of vehicle.MethodsAt the end of the dietary regimen, arterial blood pressure (ABP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, and the structure of intra-renal resistance vessels was examined by planar morphometric analysis of coronal sections prepared from perfusion-fixed kidneys.ResultsBoth 6-OHDA-treated and untreated DS rats presented a greater degree of intra-renal vessel remodelling characterized by reduced lumen diameter in the absence (eutrophic) or presence (hypertrophic) of cross-sectional area expansion, higher renal vascular resistance (RVR) and lower GFR and RBF than DR rats. Chemical sympathectomy increased lumen diameters and reduced vascular wall expansion, resulting in a decrease in RVR and a concomitant increase in RBF and GFR in both strains; however, the effect was more prominent in the DS rats.ConclusionsWe conclude that HS-LK-induced changes in intra-renal vessel structure and renal haemodynamic function in Dahl rats are, at least in part, dependent on the activity of the ympathetic nervous system.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo compare the efficacy and tolerability of angiotensin II (Ang II) antagonist losartan and the β-blocker atenolol in the treatment of patients with isolated systolic hypertension (ISH) after 16 weeks of treatment.MethodsA double-blind, randomized, multi-country study was carried out in 273 patients with ISH. Patients with a sitting systolic blood pressure (SiSBP) of 160–205 mmHg, and a sitting diastolic blood pressure (SiDBP) <90 mmHg at screening and at placebo baseline were subjected to a 4-week placebo period and then randomly grouped to receive 50 mg losartan or 50 mg atenolol once daily for 16 weeks. At 8 and 12 weeks, patients not controlled (SiDBP ⩾ 160 mmHg) were given additional treatment of 12.5 mg hydrochlorothiazide (HCTZ) once daily.ResultsSimilar significant reductions in SiSBPs (mean ± SD) were obtained with 50 mg losartan and 50 mg atenolol, from 173.7 ± 10.3 and 173.5 ± 10.7 mmHg at baseline to 149.0 ± 15.5 and 148.2 ± 15.3 mmHg after 16 weeks of losartan or atenolol treatment, respectively. Sixty-seven percent of the losartan-treated and 64% of the atenolol-treated patients remained on monotherapy throughout the study. Only 1.5% of the losartan-treated patients withdrew because of a clinical adverse event (CAE) compared with 7.2% in the atenolol-treatment group (P= 0.035). Drug-related CAEs were observed significantly more frequently with atenolol than with losartan treatment (20.3 versus 10.4%;P= 0.029).ConclusionIt is concluded that 50 mg losartan and 50 mg atenolol produced comparable reductions in SiSBP in patients with ISH but losartan was better tolerated. This is the first demonstration of the therapeutic value of selective Ang II receptor blockade with losartan in the treatment of ISH.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesFirst, to evaluate the prevalence of left ventricular (LV) hypertrophy, LV concentric remodelling and microalbuminuria in a selected sample of treated hypertensive patients with effective and prolonged clinic blood pressure (BP) control (BP <140/90 mmHg). Second, to compare the prevalence of these markers of organ damage in patients with and without ambulatory BP (ABP) control, defined as average daytime BP <132/85 mmHg).Design and methodsFifty-eight consecutive hypertensive patients who attended our hypertension outpatient clinic over a period of 3 months and were regularly followed up by the same medical team were included in the study. Obesity, diabetes mellitus, history or signs of cardiovascular or renal complications and major noncardiovascular diseases were the exclusion criteria from the study. Each patient underwent 24 h ABP monitoring, echocardiography and 24 h urine collection for albumin measurement.ResultsThe prevalence of LV hypertrophy (LV mass index >125 g/m2in both sexes), LV concentric remodelling (relative wall thickness >0.45) and microalbuminuria (urinary albumin excretion <300 mg/ 24 h) in this selected group of patients (32 men, 26 women; mean age 53 ± 9 years; mean clinic BP 122 ± 9/78 ± 6 mmHg) was markedly low (6.9, 8.6 and 5.1%, respectively).The 26 patients with effective ABP control (group I) were similar to the 32 patients without effective ABP control (group II) in age, gender, body surface area, clinic BP, smoking habit, glucose, cholesterol and creatinine plasma levels.Prevalence of LV hypertrophy, LV concentric remodelling and microalbuminuria was lower in group I than in group II (0 versus 12.9%P<0.01, 7.7 versus 9.4% NS, 3.8 versus 6.2% NS, respectively).ConclusionsThis study demonstrates that nonobese, nondiabetic hypertensive patients with an effective clinic BP control have a very low prevalence of target organ damage and that LVH is present only in individuals with insufficient ABP control.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID