ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine whether changes in haemodynamic load, simulatedin vitroby mechanically stretching cultured vascular smooth muscle cells, could be transduced into biochemical signals similar to those produced by growth factors.DesignA system was developed which was capable of stretching cultured vascular smooth muscle cells from 0 to 20%. The effect of stretching quiescent vascular smooth muscle cells on both c-fosmessenger RNA (mRNA) expression and release of total inositol phosphates was determined over a time interval of 0–360 min.MethodsRat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Induction of the proto-oncogene,c-fos,was determined by Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells.ResultsA 20% fixed stretch resulted in a rapid induction ofc-fosmRNA which reached maximal levels by 15 min. The amount ofc-fosmRNA detected was dependent on the degree of stretch, with maximum induction obtained for 15 and 20% stretch. The effects of mechanical stretch were also assessed on phosphoinositide turnover by measuring [3H]-inositol phosphates released from prelabelled cells. A 20% fixed stretch of vascular smooth muscle cells for 20 min resulted in a 3.2-fold increase in total [3H]-inositol phosphates released compared with unstretched cells.ConclusionsOur results show that mechanical stretch increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cellsin vitro.These observations suggest that mechanical stretch and growth factors share common signal transduction pathways which may be important in the development of vascular hypertrophy.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveWe examined the effects of a calcium antagonist and an angiotensin converting enzyme (ACE) inhibitor on contractile and non-contractile protein metabolism and cardiac function in a monocrotaline-induced right ventricular hypertrophy model, in order to define the effects of these drugs on cardiac hypertrophy.MethodsOne week after monocrotaline injection, male Sprague-Dawley rats were given either a calcium antagonist (nilvadipine; 3mg/kg per day) or an ACE inhibitor (delapril-HCI; 30mg/kg per day) for 2 weeks. Right ventricular pressure, the right ventricle:(left ventricle + interventricular septum) ratio, myosin isoenzymes, collagen concentration, collagen types and contractility of right ventricular free wall were examined.ResultsIn untreated rats significant monocrotaline-induced right ventricular hypertrophy with an increase in the proportion of collagen types III and V was observed. There were no significant changes in collagen concentration. Both drugs reduced right ventricular pressure to the same degree and decreased right ventricular hypertrophy. However, the inhibitory effect of delapril on right ventricular hypertrophy was stronger than that of nilvadipine. Nilvadipine reduced the collagen concentration and reversed changes in collagen types, whereas delapril did not have any significant effect on collagen concentration or collagen types. Cardiac contractility was improved by delapril, but not by nilvadipine.ConclusionsThe results show that a calcium antagonist disproportionately inhibited contractile and non-contractile protein metabolism, whereas an ACE inhibitor proportionally inhibited them and improved cardiac function in a model of right ventricular hypertrophy. The improvement in cardiac function may be due partly to the proportional inhibition of contractile and non-contractile proteins elicited by an ACE inhibitor.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo characterize endothelin-1 inactivating peptidase (ET-1 peptidase) recently isolated from rat kidney.MethodsET-1 peptidase was purified from the membranes of whole Wistar-Kyoto (WKY) rat kidneys using differential centrifugation, detergent solubilization, ion-exchange chromatography, ultrafiltration and preparative electrophoresis. The enzyme activity in the presence of increasing concentrations of unlabelled peptides, inhibitors and other substances was determined at pH 5.5 and 37°C using fixed amounts of [125I]-ET-1 as the substrate.ResultsOn non-denaturing gels, the purified enzyme migrated in the form of a compact, low-mobility (Rf 0.07), high relative molecular mass (approximately 250000) protein band. During denaturing polyacrylamide gel electrophoresis this protein separated into three fractions with apparent relative molecular masses 158 000,110 000 and 61 000. Using different buffers, the optimum pH for this enzyme was found to be 5.5. Zinc (3.7mmol/l), nickel (4.0 mmol/l), citrate (0.6mmol/l), phosphate (1.3 mmol/l) and barbital ions (2.5 mmol/l) inhibited ET-1 peptidase activity by 50%, whereas magnesium, calcium, cobalt, manganous, sodium and borate ions were without effect. The most powerful inhibitors of the enzyme included: phenanthroline [median inhibitory concentration (IC50) 28 μmol/l], phosphoramidon (IC50 8.0 μmol/l), thiorphan (IC50 32 μmol/l) andN-carboxymethyl-Phe-Leu (IC50 12 μmol/l). Also, bacitracin (25 μmol/l), cyclosporine A (20 μmol/l) and sodium dodecyl sulphate (0.5%) inhibited enzyme activity by 50%, whereas bestatin, puromycin, aprotinin, phenylmethylsulphonyl fluoride, amanitin (50–100 μmol/1) and cardiotoxin (25 μg/assay) had no effect. The Michaelis constant (Km) values of 70 and 66 nmol/l were found towards ET-1 and the ET(16–21) fragment, respectively, whereas the Km values in respect to big-ET-1, sarafotoxin S6b, sulphated cholecystokin octapeptide, gastrin, glucagon, insulin, gastric inhibitory peptide and growth hormone ranged from 1.5 to approximately 50fimol/l. The enzyme showed no apparent affinity for enkephalins, bradykinin, angiotensins, cholecystokinin tetrapeptides and kyotorphin.ConclusionsThe present data suggest that the ET-1 peptidase that we isolated from rat kidney displays inhibitory characteristics similar to that of other known metalloendopeptidases. However, this enzyme exhibits several unique properties such as high molecular mass, an apparent complex subunits structure, pH optimum at 5.5, and very high substrate specificity towards ET-1 and the ET(16–21) fragment compared with other peptides either related or unrelated to endothelin.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo investigate the role of angiotensin II (Ang II) in cardiovascular hypertrophy in the Goldblatt one-kidney, one clip (1-K,1C) renal hypertensive rat.MethodsSix-week-old Wistar-Kyoto (WKY) rats underwent uninephrectomy and left renal artery clipping. After surgery, rats were treated with perindopril, an angiotensin converting enzyme (ACE) inhibitor, or losartan, an Ang II type 1 (AT1) receptor antagonist, for 4 weeks. Untreated 1-K,1C rats and uninephrectomized (sham) rats served as controls.ResultsThe rise in systolic blood pressure in the perindopril-treated and losartan-treated rats was not significantly different from that in the untreated 1-K,1C group throughout the treatment period. At 4 weeks after surgery the heart weight:body weight ratios of the untreated 1-K,1C and losartan-treated 1-K,1C groups were significantly greater than for sham-operated normotensive rats and hypertensive perindopril-treated rats. The total number of smooth muscle cells in the thoracic aortae of the 1-K,1C untreated, losartan-treated 1-K,1C and sham groups were similar. However, after treatment the aortae of the perindopril-treated group contained significantly fewer smooth muscle cells. The medial cross-sectional wall area and wall: lumen ratio were similar in the 1-K,1C untreated and perindopril-treated 1-K,1 C groups.ConclusionThese results suggest that Ang II, via its effects on cardiac and vascular AT1 receptors, does not contribute to the development of cardiovascular hypertrophy in the 1-K,1C rat. Attenuation of cardiac and vascular growth after ACE inhibition appears to be mediated by mechanisms independent of the actions of the renin-angiotensin system.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveDespite the return of mean arterial pressure (MAP) to control levels, aortic depressor nerve activity remains elevated from control levels after sustained phenylephrine-induced increases in MAP in spontaneously hypertensive rats (SHR) (Kenney MJ, Morgan DA, Mark AL:Am J Physiol1990, 258:H1476-H1481). This suggests that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR. However, because phenylephrine can exert an excitatory effect on the aortic arch baroreceptors, the increase in aortic depressor nerve activity might have resulted from a persistent direct effect of phenylephrine. The aim of the current study was to determine whether elevations in MAP induced by aortic occlusion produce increases in aortic depressor nerve activity which persist after the return of MAP to control levels.MethodsMAP and aortic depressor nerve activity were recorded before, during and after sustained (15–30min) periods of aortic occlusion in SHR with intact adrenal glands (n = 18) and in adrenalectomized SHR (n = 10). Control experiments were completed in which the same variables were recorded before, during and after sham aortic occlusion in intact (n = 8) and adrenalectomized (n = 8) SHR.ResultsAortic occlusion increased MAP and aortic depressor nerve activity significantly from control levels. After aortic occlusion and the return of MAP to control levels, aortic depressor nerve activity remained significantly increased in 15 experiments, whereas in three experiments aortic depressor nerve activity was reduced. Aortic depressor nerve activity was increased significantly from control levels after aortic occlusion in adrenalectomized rats. Aortic depressor nerve activity remained unchanged from control levels after sham aortic occlusion in intact and adrenalectomized SHR.ConclusionsSustained elevations in MAP induce increases in aortic depressor nerve activity in intact and adrenalectomized SHR, which persist after the return of MAP to control levels. These observations suggest that sustained increases in arterial pressure may produce prolonged pressure-induced changes in afferent baroreceptor nerve activity in SHR.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveWe postulated a 'kinin-tensin system' in which angiotensin II (Ang II) is cleaved by one or more serine protease independent of renin or angiotensin converting enzyme (ACE). The aim was to determine whether this alternative Ang II-forming pathway by serine proteases participates in the rise in plasma levels of Ang II during exercise in humans.Design and methods: The study consisted of two double-blind crossover experiments. In experiment 1 six healthy volunteers who had been taking either placebo (group P) or the ACE inhibitor captopril (150mg/day for 3 days; group C) performed a cycle ergometer graded exercise test at four different exercise intensities: stage 1, half of the intensity at the blood lactate threshold (WLt); stage 2, the intensity at WLt; stage 3, the intensity at 4mmol/l blood lactate; and stage 4, an intensity between stage 3 and maximum intensity. In experiment 2 the same volunteers took captopril (150mg/day for 3 days) and performed exercise at an intensity corresponding to 90% of the 4 mmol/l blood lactate intensity for 30 min during intravenous drip injection of a serine protease inhibitor, nafamostat [NAF; 0.2 mg/kg per h; NAF(+) group] or saline [NAF(-) group].ResultsIn experiment 1 plasma Ang II levels increased from at rest to after exercise in both groups P and C. Although there was a significant treatment effect, captopril did not significantly alter the exercise-induced changes in Ang II level. In experiment 2 the increase in Ang II level after 30 min exercise in the NAF(+) group was significantly lower than in the NAF(-) group.ConclusionsThese results suggest the presence of an alternative Ang II-forming pathway independent of ACE, and that one or more NAF-sensitive serine protease is responsible, at least partly, for generating Ang II during exercise.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo study the association between blood pressure and change in blood pressure with future coronary risk among elderly men.DesignCohort study.Setting: Finnish cohorts of the Seven Countries Study.Participants: Four hundred and seventy-six men aged 65–84 years and free of clinically manifested coronary heart disease at baseline, in 1984.Main outcome measures: Fatal myocardial infarction (n = 29), any myocardial infarction (n = 42), and incidence of any new signs and symptoms of coronary heart disease (n = 80) during a 5-year follow-up.ResultsIn multivariate analysis, a significant inverse U-shaped relationship was observed between baseline diastolic blood pressure and future fatal myocardial infarction, any myocardial infarction and any coronary heart disease. In models predicting the risk of coronary heart disease during 1984–1989, there was a significant interaction between both systolic (SBP) and diastolic blood pressure (DBP) in 1969–1974 and change in blood pressure between 1969–1974 and 1984. In categorical analyses, men (n = 42) who experienced a decline in DBP of ≥4mmHg from initial levels of ≥90 mmHg had a higher risk of any myocardial infarction than men (n = 112) with a change of <4 mmHg (odds ratio 4.5). For a decline of ≥10 mmHg or more in SBP from levels of ≥160 mmHg the corresponding odds ratio was 2.9. Men who experienced a decline in DBP or SBP from normotensive levels or an increase in blood pressure had no excess risk compared with men with stabile (change in DBP <4mmHg and change in SBP <10mmHg) blood pressure values.ConclusionThe present results suggest that among elderly men a decline in DBP or SBP from previously hypertensive levels may be associated with increased coronary risk.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectivesTo study the relationship between serum insulin and blood pressure, as well as the prevalence of hypertension according to the insulin level in a general Japanese population.DesignIn 1988 a cross-sectional community survey was conducted among Hisayama residents aged 40–79 years.MethodsA total of 1073 males and 1407 females (72.5 and 80.5% of the total population, respectively) underwent comprehensive investigation, including a 75-g oral glucose-tolerance test. Fasting and 2-h serum insulin levels were measured by radioimmunoassay.ResultsThe sum of the fasting and 2-h postloading insulin levels was significantly correlated with the systolic blood pressure (SBP; r = 0.18 and 0.26 for males and females, respectively) and the diastolic blood pressure (DBP; r = 0.24 and 0.19, respectively) in the subjects not receiving antihypertensive drugs. In multiple regression analysis the correlation with blood pressure remained significant in both sexes even after controlling for age, body mass index, alcohol intake, smoking, a family history of hypertension, serum total cholesterol and fasting plasma glucose. The age- and sex-adjusted prevalence of hypertension (SBP ≥ 160mmHg or DBP ≥ 95mmHg, or both, or receiving drug treatment) increased significantly with an increase in the sum of fasting and 2-h postload insulin levels in both the non-obese subjects (body mass index <25 kg/m2) and the obese subjects (body mass index ≥ 25kg/m2). Multiple logistic regression showed that the sum of fasting and 2-h postload insulin levels was a significant factor with an independent relationship to hypertension, even after taking the other risk factors into account.ConclusionThe present study suggests that hyperinsulinaemia is related to hypertension in a general Japanese population.

ISSN:0263-6352    

出版商:OVID    

年代:1994

数据来源: OVID