ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundEvidence-based medicine (EBM) has been propagated as a revolutionary development which will improve the quality of clinical decision-making and guideline development. Historically it follows an early 19th century French attempt to introduce mathematical analysis into clinical practice. This met with resistance from both clinicians and scientists and was only accepted in more recent times with the development of clinical epidemiology and clinical trials.Nature of EBMEMB claims to utilize the best available evidence to reach scientific conclusions, rejecting the appeal to expert authority. This involves a hierarchy of sources which places large controlled trials at the apex. Less value is attributed to arguments from clinical observation or pathophysiology. Systematic reviews and meta-anlyses of trials therefore provide the strongest evidence for clinical decisions.The concept of evidenceThe approach advocated in EBM is an over-simplification of the process of clinical thinking which involves interpretation and synthesis of relevant evidence from all sources and extrapolation to the clinical situation. In this process, there is no hierarchy of evidence. The relative value given to any particular evidence depends more upon its relevance and persuasiveness than the category to which it belongs. Discussion and debate amongst informed ‘experts’ is an integral feature of this process at each stage.Impact of EBMAlthough advocates of EBM acknowledge the contribution of all forms of evidence, the differential value attached to different sources has led to naïve and simplistic attempts to omit the traditional processes of interpretation, synthesis and extrapolation and to draw wide-ranging conclusions from trial data without adequate scientific discussion.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. Over the past decade, evidence has accumulated indicating that short-term insulin administration, in addition to its metabolic effects, also has important cardiovascular actions. The sympathetic nervous system and the L-arginine-nitric oxide pathway have emerged as central players in the mediation of insulin's cardiovascular actions. The underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant subjects. Here we summarize the current understanding and gaps in knowledge on insulin's cardiovascular actions in humans, and discuss possible pathophysiological consequences of their alteration. Based on recent new insight, we propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

MethodsBlood pressure variability was evaluated in conscious Wistar control rats and rats with established L-NAME hypertension (20 mg/kg per 24 h, 4 weeks).ResultsFinal systolic arterial pressure was 185 ± 5 and 132 ± 4 mmHg in the Nω-nitro-L-arginine methyl ester (L-NAME)-treated and control rats, respectively. The standard deviation of systolic arterial pressure in the L-NAME group was 70% greater than in the control rats, indicating a significant increase in the overall variability. Arterial pressure in the L-NAME rats exhibited aperiodical, abrupt rises and falls and data was grossly non-stationary. Blood pressure variability was therefore evaluated using Poincaré plot analysis. The variance of the difference (delta) between two successive values of systolic arterial pressure, determined for time intervals of 0.2 to 5 s (0.2 s increment), was always significantly higher in the L-NAME group compared with untreated animals. The variance of delta systolic arterial pressure increased with the time interval and plateaued for time intervals of 2.4 and 1.4 s in hypertensive and normotensive rats, respectively. These differences vanished when the sudden events oberved in L-NAME rats were omitted in the construction of Poincaré plots. Acute administration of prazosin (1 mg/kg), but not losartan (10 mg/kg) markedly reduced the variance of delta systolic arterial pressure in hypertensive rats.ConclusionsNitric oxide participates in the control of arterial pressure variability. The sympathetic nervous system seems to be a major determinant of the increased short-term variability of arterial pressure in this model.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTransforming growth factor-β1 (TGF-β1) stimulates vascular smooth muscle cell growth in spontaneously hypertensive rats (SHR), but inhibits cell growth in normotensive Wistar-Kyoto (WKY) rats. The present study was undertaken to test the hypothesis that TGF-β1 might differentially modulate the activities of mitogen-activated protein (MAP) kinase family members (ERK, JNK and p38) in vascular smooth muscle cells of SHR and WKY rats.MethodsMAP kinase activity was measured from cultured vascular smooth muscle cells in response to TGF-1 by specific substrate phosphorylation of myelin basic protein, GST-c-Jun and GST-ATF2.ResultsExposure of cultured vascular smooth muscle cells from SHR or WKY rats to TGF-β1 resulted in a marked increase in the activity of ERK, but not of JNK or p38. The increase of ERK activity stimulated by TGF-β1 appeared similar in time course and extent in both WKY and SHR cells, with increased activity peaking at 15 min of incubation. Epidermal growth factor (EGF) also stimulated the activity of ERK, in both WKY and SHR cells, but nor of JNK or p38, with stimulation of ERK activity by EGF occurring more rapidly in SHR cells than in those from WKY rats. Co-incubation of SHR cells with TGF-β1 and EGF showed additive effect on ERK activity.ConclusionsThe results provide the first evidence that TGF-β1 activates ERK in vascular smooth muscle cells of both normotensive and hypertensive rats. The matching response of ERK activation to TGF-1 in SHR cells suggests that the MAP kinase-signaling pathway remains largely unchanged in the regulation of vascular smooth muscle growth by TGF-1 in spontaneously hypertensive rats.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression.MethodsSpontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared.ResultsLosartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments.ConclusionsOur results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1receptor antagonism and ACE inhibition.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThe effects of short-term administration of dexamethasone on sodium/proton antiporter (Na+/H+antiporter) in human lymphocytes were investigatedin vitro.MethodsCytosolic pHiin lymphocytes was measured spectrophotometrically using the pH-sensitive fluorescent dye 2′-7′-bis-carboxyethyl-5(6)-carboxyfluorescein at 530 nm with excitation wavelengths of 440 and 530 nm. The Na+/H+antiporter activity was determined after intracellular acidification using 100 mmol/l propionic acid.ResultsThe addition of 1 μmol/l dexamethasone significantly reduced cytosolic pHifrom 7.44 ± 0.03 to 7.25 ± 0.05 (mean ± SEM;P< 0.01). Incubation with dexamethasone for 40 min significantly reduced the Na+/H+antiporter activity from (9.19 ± 0.61) × 10−3pHi/s (n= 22) to (7.23 ± 0.49) × 10−3pHi/s (n= 22;P< 0.01). The effect of dexamethasone was time and concentration dependent. The apparent affinity of the Na+/H+antiporter was not significantly different in the absence or presence of dexamethasone. The inhibition of the Na+/H+antiporter by dexamethasone was abolished in the presence of the glucocorticoid receptor blocker, mifepristone.ConclusionDexamethasone directly inhibits the Na+/H+antiporter using a receptor-dependent pathway. This effect may be important for pharmacological side effects such as glucocorticoid-induced hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo study whether heredity for hypertension influences intra-uterine growth and the relationship between fetal growth and adult blood pressure.DesignFive-year prospective follow-up study with retrospective collection of data on size at birth and gestational age from obstetric records.SettingCentre of preventive medicine in Malmö, Sweden.SubjectsThirty normotensive men with and 27 without heredity for hypertension were investigated in 1990, and the majority (n= 28 andn= 20, respectively) in 1995 also.Main outcome measuresTwo measures of intra-uterine growth were compared between the groups and related to adult systolic blood pressure: the birth weight deviation from the expected birth weight based on ultrasonically derived intra-uterine growth curves, and the degree of thinness at birth (ponderal index = weight/length3).ResultsThe birth weight deviation in men with heredity for hypertension differed significantly from that in men without such heredity (%) (−6.9 ± 12.0 versus +7.3 ± 18.4;P= 0.002). Ponderal index was somewhat lower in the men with than in those without heredity for hypertension, but the difference did not reach statistical significance (kg/m3) (25.9 ± 2.6 versus 27.0 ± 2.2;P= 0.08). In the group with heredity for hypertension, systolic blood pressure correlated inversely with ponderal index both in 1990 (r= −0.44;P= 0.01) and 1995 (r= −0.49;P= 0.009), and the 5-year increase in systolic blood pressure correlated inversely with the birth weight deviation (r= −0.38;P= 0.04). No such correlations were found in the group without heredity for hypertension.ConclusionOur results suggest that genetic factors contributing to the development of hypertension may influence intra-uterine growth.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveAldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, the T allele of a polymorphism in the 5′-flanking region of theCYP11B2gene (C-344T) has been reported to be more frequent in hypertensives than in normotensives, and has also been associated with increased plasma aldosterone levels. We therefore hypothesized that this variant may be related to increased blood-pressure response to dietary salt intake.Subjects and methodsWe genotyped 163 young normotensive men recruited within the framework of the Berlin Salt-Sensitivity Trial (BeSST) for theCYP11B2C-344T polymorphism. Subjects were characterized for family history of hypertension, plasma parameters of the renin-angiotensin-aldosterone system and blood-pressure response to a high (220 mmol/day) and low (20 mmol/day) salt diet.ResultsThe frequency of the −344T allele (0.45) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (CC,n= 55; CT,n= 71; TT,n= 37). There was a trend towards a higher frequency of the T allele in subjects with a positive family history of hypertension (0.48 versus 0.42), but the C-344T genotype was not related to blood pressure under either diet. Furthermore, when subjects were classified into salt-sensitive and salt-resistant groups, allelic distribution did not differ between the two groups (qT = 0.43 versus qT = 0.45). While renin activity and plasma aldosterone levels were not related to genotype, plasma angiotensinogen was significantly higher in T-allele carriers under both the high (P= 0.02) and low (P= 0.008) salt diet.ConclusionOur findings do not support the hypothesis that the C-344T polymorphism of theCYP11B2gene is associated with salt sensitivity or increased activity of the renin-angiotensin system in young normotensive subjects. It is, therefore, unlikely that the C-344T polymorphism is a genetic marker for salt sensitivity in young normotensive Caucasian men.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population.Patients and methodsThe insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study.ResultsThe DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09–2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, Cl = 1.01–2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, Cl = 1.09–4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3′-microsatellite polymorphism of the AGT gene and hypertension.ConclusionThe D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3′-microsatellite polymorphism of the AGT gene and hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID