摘要:

Several lines of evidence suggest that insulin resistance and the resultant hyperinsulinaemia are causally related to hypertension. Insulin actions are initiated by binding to a high-affinity transmembrane protein receptor which is present in all mammalian cells. These effects are predominant in skeletal muscle, liver, and fat and involve a number of tissue-specific and biochemically diverse events. Less well known are effects of insulin occurring in tissues not usually considered as insulin targets, which are hypothetical contributors to the pro-hypertensive action of the hormone. These effects include activation of renal sodium reabsorption, stimulation of the sympathetic nervous system, growth-promoting activity on vascular smooth muscle cells, and modulation of transmembrane cation transport. Epidemiological investigations have implicated sodium intake in the pathogenesis of hypertension. Because of the sodium-retaining effects of insulin, it has been postulated that insulin resistance with associated hyperinsulinaemia may be critical for the pathogenesis of salt-sensitivity in essential hypertensive subjects. Insulin resistance is present also in strains of rats with genetic hypertension that can be utilized as models to study the molecular mechanisms of this abnormality. In the present article, we summarize the current knowledge of the mechanisms of insulin resistance in rat models of arterial hypertension in which decreased sensitivity to insulin occurs and propose a rationale hypothesis that links insulin resistance with salt-sensitivity and hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveEpidemiological studies suggest that intrauterine growth restriction (IUGR) due to maternal undernutrition during pregnancy represents a major risk factor for hypertension and diabetes in adult age. However, placental insuficiency, rather than maternal malnutrition, is the main cause of IUGR in the Western world. We therefore studied the relationship between birth weight and adult blood pressure and glucose tolerance in an established animal model of placental insufficiencyDesignIUGR was induced by uterine artery ligation in pregnant rats and the offspring were studied at 3–4 months of age.MethodsIn one subgroup of animals (n= 41, birth weight range 3.2–6.6 g) blood pressure was recorded over 72 h using telemetry and hypothalamic tissue levels of noradrenaline was measured. In another subgroup (n= 30, birth weight range 3.0–6.8 g) the activity of the sympathetic nervous system (SNS) was assessed by noradrenaline isotope dilution techniques and glucose tolerance determined by an intravenous glucose load.ResultsAdult blood pressure was independent of birth weight. Haemodynamic responses of IUGR rats to moderate sound stress was unaltered. In male rats neither SNS activity, hypothalamic noradrenaline concentrations nor glucose tolerance was associated with birth weight. In contrast, IUGR in female rats was associated with increased SNS activity, elevated fasting blood glucose as well as lower insulin and higher glucose levels in response to a glucose load.ConclusionIUGR is not linked to an elevated blood pressure at 3–4 months of age in this model. However, in female rats, IUGR is associated with increased SNS activity and impaired glucose tolerance in adult life.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveRecently, we observed that recombinant human erythropoietin (rHuEPO) inhibits the interleukin (IL)-1β induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in cultured rat vascular smooth muscle cells (VSMC). The mechanisms of these inhibitory effects of rHuEPO were evaluated.MethodsReverse transcription-polymerase chain reaction (RT-PCR) was performed to identify a specific erythropoietin receptor (EpoR). Tyrosine phosphorylation of phospholipase C (PLC) was analyzed by combination of immunoprecipitation and Western blotting. Protein kinase C (PKC) activities were analyzed by phosphorylation assay of myelin basic protein (MBP4-14). VSMC were incubated with test agents for 24 h and nitrite as a stable NO metabolite was measured. iNOS mRNA and protein expression was analyzed by Northern and Western blotting, respectively.ResultsRT-PCR analysis revealed that EpoR m-RNA was expressed; furthermore, it might be alternatively spliced in VSMC. rHuEPO induced tyrosine phosphorylation of PLC-γ1 and activation of PKC. rHuEPO inhibited not only IL-1β induced nitrite production, but also the expression of iNOS mRNA and protein. These inhibitory effects of rHuEPO were reversed in the presence of PKC inhibitors, calphostin C (1 μmol/l) orstaurosporine (10 nmol=l). PKC activation by phorbol myristate acetate inhibited nitrite production. The inhibitory effect of rHuEPO on IL-1β induced nitrite production was also eliminated in PKC depleted cells or in the existence of anti-EpoR antibody.ConclusionrHuEPO inhibits IL-β induced NO production by suppressing iNOS mRNA and protein expressions through EpoR, and the PLC-γ1 and PKC pathway may be involved.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo study whether abnormalities of autonomic function exist in patients with essential hypertension and neurovascular compression (NVC) of the medulla oblongata.Subjects and methodsWe studied 25 untreated patients with essential hypertension (13 men and 12 women, 27–74 years old). High-resolution magnetic resonance imaging and magnetic resonance angiography were used to detect NVC. Twenty-four-hour ambulatory monitoring of blood pressure and electrocardiogram were performed, and the power spectrum of heart rate variability was analyzed. On a separate day, various autonomic activity tests, including mental stress, hand grip, cold pressor, and Valsalva maneuver were performed. Baroreflex sensitivity was calculated from changes of blood pressure and R-R interval during phenylephrine infusion. A clonidine suppression test was also performed, with measurement of plasma catecholamine levels.ResultsFourteen of 25 patients (56%) had NVC (C group), and 11 patients did not have NVC (NC group). There were no significant differences in age, sex, family history, or duration of hypertension between the C and NC groups. Average 24-h systolic blood pressure was similar between the two groups, although 24-h diastolic blood pressure was higher in the C group than the NC group. Daytime, night-time, and 24-h heart rate was significantly higher in the C group than in the NC group. Night-time low frequency/high frequency ratio was slightly higher in the C group. Plasma norepinephrine levels were significantly higher (467 ± 217 versus 299 ± 122 pg/ml), and baroflex sensitivity was slightly lower in the C group than in the NC group. Responses of blood pressure and heart rate to mental stress, cold pressor, hand grip, Valsalva maneuver, phenylephrine infusion, and clonidine tests were not significantly different between the two groups.ConclusionsNVC of the medulla oblongata was frequently found in patients with essential hypertension. Patients with NVC appeared to have enhanced sympathetic nervous activity compared with those without the compression.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThe presence of bradykinin B2 receptors in the cardiovascular regulatory centres of the brain indicates that increase in mean arterial pressure (MAP) and heart rate after intracerebroventricular (i.c.v.) injections of bradykinin is mediated via stimulation of sympathetic nervous system.MethodsAdult Wistar–Kyoto (WKY) rats were instrumented chronically with an i.c.v. cannula, and the catheters were placed into the femoral artery and vein. Increasing doses of bradykinin (1–300 pmol) were given i.c.v. and (i) MAP and heart rate, (ii) plasma dopamine, noradrenaline and adrenaline, and (iii) plasma arginine vasopressin (AVP) levels were determined. In addition, following blockade of peripheral α1-adrenoceptors with prazosin (50 and 250 μg/kg i.v.) β1-adrenoceptors with atenolol (10 mg/kg i.v.) or V1-receptors with TMe-AVP (Manning compound) (10 μg/kg i.c.v. and 100 μg/kg i.v.) the effects of bradykinin (100 pmol i.c.v.) on MAP and heart rate were determined.ResultsBradykinin increased MAP and heart rate dose-dependently. The pressor effects of 100 pmol bradykinin i.c.v. were completely blocked by pretreatment with the specific B2receptor antagonist Hoe 140 (3 pmol, i.c.v.). There was no change in plasma dopamine, noradrenaline, adrenaline or AVP levels after increasing doses of bradykinin. However, peripheral blockade of α1- and β1-adrenoceptors reduced the bradykinin-induced increase in MAP and heart rate, whereas central and peripheral V1receptor blockade did not alter the cardiovascular responses to i.c.v. bradykinin.ConclusionOur data suggest that the hypertensive and positive chronotropic effects induced by i.c.v. bradykinin are due to stimulation of sympathoneuronal rather than sympathoadrenal pathwayin vivo. J Hypertens1999, 17:1265–1271 © Lippincott Williams & Wilkins.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo study insulin resistance in subjects with strong genetic predisposition to essential hypertension compared with non-disposed subjects.SubjectsThirty normotensive subjects aged 18–35 years whose parents both had essential hypertension, and 30 age- and sex matched subjects whose parents were both normotensive, were studied. Subjects or parents with diabetes and morbid obesity were excluded.MethodsThe study comprised (1) a frequent sampling oral glucose tolerance test; (2) an isoglycemic hyperinsulinemic clamp study; (3) an analysis of body composition by dual-energy X-ray absorptiometry; (4) an exercise test with gas exchange analysis; and (5) investigation of composition of usual diet by diet registration for 5 days.ResultsThe 24-h diastolic blood pressure was higher in subjects predisposed to hypertension compared with the controls: 78.1 versus 74.0 mmHg (confidence interval for the difference between the means; −0.5; −7.9), but the insulin sensitivity index was similar: 312 versus 362 l2min−1pmol−1kg−1(28; −129). The two groups were similar in terms of body composition, exercise capacity and composition of usual diet. Resting and 24-h diastolic blood pressures were correlated to abdominal fat mass but not to insulin sensitivity.ConclusionSubjects with a strong genetic predisposition to essential hypertension had increased diastolic blood pressure compared with subjects with normotensive parents, but they were not insulin resistant. This may be due to the subjects being highly selected as to confounding factors. The increased blood pressure in the hypertension prone subjects could not be attributed to differences in body composition, exercise capacity or dietary habits. J Hypertens 1999,17:1273–1280 & Lippincott Williams & Wilkins.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundEssential hypertension is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has incriminated endothelin-2 (ET2) as a candidate gene for human essential hypertension. This study sought to (i) determine the existence of any molecular variants in the ET2 gene; (ii) undertake an allelic-association study of any such variants found in a large group of well characterized hypertensive and control populations; and (iii) assess any quantitative relationship between the molecular variant and pretreatment blood presure.MethodsThe ET2 gene was subjected to single strand conformation polymorphism (SSCP) analysis in order to identify novel molecular variants. Well-characterized subjects recruited from our local population were used in our association study. Two hundred and forty-four hypertensive patients with pre-treatment blood pressure (range 139/94-237/133 mmHg) were well matched with 228 controls from our local population of 30 000 healthy subjects (range 96/62-160/85 mmHg). All subjects were Caucasian.ResultsPolymerase chain reaction-SSCP identified a single A985G base change in 3′-UTR of the ET2 gene which was conirmed by direct sequencing. A restriction site for the enzyme BsmA1 was either created (+) or removed (2) with this polymorphism. Analysis of variance showed that the ET2 genotype was an independent predictor of pre-treatment diastolic blood pressure (DBP) in the hypertensive (P < 0.001) but not normotensive group with higher pressures tracking with the (−) allele. Other covariates such as age, sex, alcohol, cigarette smoking, body mass index and cholesterol showed no significant relationship with this genotype. The genotype frequencies for the hypertensive and control population were (−/−: −/+: +/+) 178:58:8 and 168:55:5, respectively (not significant). Subjects from the top and tail quartiles of measurement of blood pressure in both groups were selected for genotype and allele frequency comparison. Both genotype and allele differences were highly significant between the two extreme groups for DBP (genotype P < 0.001, alleles P < 0.01) distribution. A search for potential functional variants in linkage disequilibrium with A985G found one further variant in the 59-UTR, C44T. Conditional haplotype probabilities in 214 chromosomes show that this polymorphism is not in linkage disequilibrium with the 39-UTR. No other variants were found on a molecular screen of the transcribed portion of the ET2 gene.ConclusionThis newly identified polymorphism of the ET2 gene tracked significantly in hypertensives when blood pressure was assessed as a quantitative trait. The difference in genotype and allele frequencies between the extremes of blood pressure suggest that the ET2 locus influences the severity rather than the initial development of hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectivePrevious studies on humans have reported higher leptin levels in women than in men, independent of body fat, and leptin has been correlated with insulin resistance in men but not in women. Since insulin resistance is thought to play a role in raising blood pressure, we investigated sex differences in leptin concentrations between hypertensive and normotensive individuals.MethodsNinety-two nondiabetic hypertensive patients (48 men and 44 women) and 92 age, body mass index (BMI)-matched normotensive control individuals were studied. Fasting plasma glucose, insulin, leptin and lipoprotein concentrations, glucose and insulin responses to 75 g oral glucose tolerance test (OGTT) and insulin suppression tests were determined.ResultsFasting plasma leptin concentrations were higher in hypertensive men than in normotensive men (5.1 ± 0.5 versus 3.9 ± 0.4 ng/ml,P= 0.015). However, fasting plasma leptin concentrations were not significantly different between hypertensive and normotensive women (11.8 ± 1.0 versus 10.9 ± 1.0 ng/ml,P= 0.440). Fasting plasma leptin concentrations showed good correlation with BMI, body fat, fasting plasma insulin concentrations, and insulin area to OGTT in both men and women (allP< 0.001). However, fasting plasma leptin concentrations were related to steady-state plasma glucose (SSPG) concentrations, a measure of insulin sensitivity by insulin suppression test, in men only (P< 0.001). After adjustment for body fat amount, age and duration of hypertension, fasting plasma leptin levels still correlated significantly with SSPG concentrations in men. These four variables together accounted for a 67.9% variation in fasting plasma leptin levels in men. In women, body fat amount was the only significant determinant for plasma leptin levels. These four variables accounted for a 78.2% variation in plasma leptin levels in women.ConclusionsOur study confirmed a sex difference in leptin levels both in hypertensive and normotensive subjects. Higher plasma leptin concentrations in hypertensive men but not in hypertensive women when compared with normotensive control individuals was also demonstrated. These observations are consistent with the findings that plasma leptin is correlated with insulin sensitivity in men but not in women. Further studies are needed to understand the causes and consequences of sex effects on leptin in blood pressure regulation.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectivePatients with obstructive sleep apnea are often obese. Obesity may contribute to both sleep apnea itself and to the cardiovascular risk associated with sleep apnea. Weight loss in obese patients with sleep apnea may alleviate symptoms and decrease the severity of sleep apnea. Whether patients with obstructive sleep apnea are indeed predisposed to recent weight gain, as compared with similarly obese subjects without sleep apnea, is not known.Patients and methodsWe compared 1-year weight histories in 53 male and female patients newly diagnosed with obstructive sleep apnea, compared with 24 controls matched for gender, age, body mass index, and percent body fat. Sleep apnea patients had never been treated. Control subjects were proven to be free of sleep-disordered breathing by overnight polysomnography.ResultsPatients with obstructive sleep apnea (n= 53) had a significant recent weight gain of 7.4 ± 1.5 kg compared with a weight loss of 0.5 ± 1.7 kg (P= 0.001) in similarly obese controls (n= 24). Male patients with obstructive sleep apnea (n= 28) had a history of significant weight gain (6.8 ± 2.3 kg) over the year preceding the study compared with male control subjects (n= 13), in whom average weight fell by 0.58 ± 2.4 kg (P= 0.03). Female patients (n= 25) with obstructive sleep apnea had an 8.0 ± 1.9 kg weight gain compared with female controls (n= 11) who had a history of weight loss of 0.46 ± 2.6 kg (P= 0.02).ConclusionThese findings support the concept that patients with obstructive sleep apnea may be susceptible to increasing obesity in the period preceding the diagnosis of obstructive sleep apnea.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective and designThe clearance receptor for natriuretic peptides (NPRC), a candidate gene for essential hypertension, is highly expressed in adipose tissue, where is nutritionally regulated. The objectives of the present study were to sequence the human 5'flanking regulatory region of NPRC, to identify allelic variants and their frequencies, and to study the genotype/phenotype correlation in hypertensive patients.Methods and resultsUsing polymerase chain reaction (PCR) and direct automated sequencing, a biallelic (A/C) polymorphism was detected at position −55 in a conserved promoter element named P1. The novel C(−55) variant makes the promoter sequence identical to the mouse gene and introduces a secondHgaIsite in the amplified DNA, allowing the genotyping of a large number of subjects. In a random sample of 232 white Caucasians the C(−55) allele was more commonly found (81.7% of all alleles) with 155 CC (66.8%), 69 AC (29.7%) and only eight AA (3.5%) genotypes. Atrial natriuretic peptide (ANP) levels were determined in 84 patients with essential hypertension. In the presence of obesity (body mass index (BMI) ≥ 30 kg/m2) the homozygous CC hypertensives (n= 21) had significantly lower plasma ANP (33.6 ± 11.1 pg/ml) compared with the AC patients (n= 11; 46.8 ± 15.9 pg/ml;P= 0.01), whereas systolic blood pressure (SBP) and mean blood pressure (MBP) had the opposite association (SBP 163.9 ± 18.7 versus 150.9 ± 12.9 and MBP 123.3 ± 12 versus 114.5 ± 5.9 mmHg;P< 0.05). The difference in ANP levels were also present when overweight patients (BMI ≥ 27 kg/m2) were considered.ConclusionA common ‘ancestral’ C(−55) variant of the NPRC P1 promoter is associated with lower ANP levels and higher SBP and MBP in obese hypertensives. The C(−55) variant, in the presence of increased adiposity, might reduce plasma ANP through increased NPRC-mediated ANP clearance, contributing to higher blood pressure.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID