摘要:

ObjectiveStudies of cerebral arterioles have suggested that pulse pressure may be a more important determinant of small-artery structure than systolic, diastolic or mean blood pressure in stroke-prone spontaneously hypertensive rats and in rats with an arterio-venous shunt. A study of small arteries has suggested that this is not the case in human essential hypertension. We therefore investigated the role of hemodynamic determinants on small-artery structure in hypertensive patients.Design and methodsTo determine whether pulse pressure contributes to structural alterations in human essential hypertension, small arteries (lumen < 300 μm) were obtained from gluteal subcutaneous biopsies of 40 normotensive subjects aged 40.7 ± 1.2 years and 45 untreated essential hypertensive humans aged 46.5 ± 1.3 years. The relationship between the media: lumen ratio of the small arteries and levels of systolic, diastolic and mean blood pressure and pulse pressure was investigated.ResultsThe media: lumen ratio (5.33 ± 0.001%) of small gluteal subcutaneous arteries of normotensive subjects was significantly smaller and the lumen diameter (306 ± 13 μm) significantly larger than in untreated hypertensive patients (7.42 ± 0.001% and 244 ± 9.7 μm respectively,P< 0.001). The media: lumen ratio of both groups examined together correlated with systolic blood pressure (r= 0.45,P< 0.001), diastolic blood pressure (r= 0.56,P< 0.001) and mean arterial pressure (r= 0.55,P< 0.001). The media: lumen ratio of vessels from hypertensive patients correlated with diastolic blood pressure (r= 0.22,P< 0.01) but not with systolic or mean blood pressure. There was no correlation between the media: lumen ratio of small gluteal subcutaneous arteries and pulse pressure in this population of normotensive and hypertensive subjects, examined together or separately.ConclusionThese results suggest that in 30- to 65-year-old humans with systolodiastolic essential hypertension, pulse pressure does not appear to be an important determinant of small-artery structure.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectivesTo measure in-vitro responses to the thromboxane A2(TxA2) mimetic U46619 in the fetal placental vasculature of human placentae from normotensive women and those with pre-eclampsia. Furthermore, to compare fetal vascular responses to endothelin-1, 5-hydroxytryptamine, potassium chloride (KCl) and prostacyclin (PGI2) in placentae from normal or pre-eclamptic pregnancies.MethodsSingle placental lobules of intact placentae were bilaterally perfusedin situ(fetal and maternal) with constant flows of Krebs' solution. Changes in fetal arterial perfusion pressure during intra-arterial infusion of vasoactive agents were recorded. Fetal placental vasoconstrictor concentration response curves were obtained to U46619 (0.01–300 nmol/l), endothelin-1 (0.4–160 nmol/l), KCl (3–300 mmol/l) and 5-hydroxytryptamine (0.03–30 μmol/l). In addition, vasodilator concentration response curves were obtained for PGI2(1.2–350 nmol/l) in the fetal placental circulation during submaximal increases in perfusion pressure with prostaglandin F2α(PGF2α; 0.7–2.0 μmol/l).ResultsThe maximum increase in perfusion pressure caused by U46619 in placentae from normotensive women was 194 ± 25 mmHg. The maximum response to U46619 was significantly reduced in the placentae from women with pre-eclampsia (104 ± 21 mmHg). In contrast, there were no differences in constrictor responses to endothelin-1, 5-hydroxytryptamine and KCl, or in dilator responses to PGI2in placentae obtained from either normotensive women or those with pre-eclampsia.ConclusionTxA2receptor-mediated vasoconstriction is reduced in the fetal vasculature of placentae from women with pre-eclampsia, possibly to compensate for the increased levels of TxA2seen in these conditions.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThis study was designed to demonstrate that the principle of molecular recognition underlying high-affinity binding of angiotensin II to the type 2 (AT2) receptor is distinct from that of the type 1 (AT1) receptor. In general, the same functional pharmacophores in hormones are used to bind and activate different subtypes of cell surface receptors. However, the binding of angiotensin II to the AT2receptor is distinct from that of the AT1receptor.Design and methodsTo systematically evaluate the effect of modification of angiotensin II side chains on binding to both the receptors, several analogs of angiotensin II were synthesized. Rat AT1or AT2receptors expressed in COS1 cell membranes were used to determine the affinity of analogs using radioligand competition binding experiments under equilibrium conditions.ResultsModifications of all angiotensin II side chains affected binding to the AT2receptor to nearly similar extents. In contrast, binding to the AT1receptor was significantly affected by modifications at side chain positions 2, 4, 6 and 7. In accordance with previous observations that Tyr4-or Phe8-modified angiotensin II analogs antagonized vasoconstriction mediated exclusively by the AT1receptor, binding to the AT1receptor was significantly dependent on Tyr4or Phe8of angiotensin II whereas binding to the AT2receptor was not. Rather surprisingly, the affinity profile of several angiotensin II analogs towards the AT2receptor was similar to the measured affinity of the constitutively active N111G mutant AT1receptor.ConclusionsThese results suggest that the AT2-receptor pharmacophore is very distinct from that of the AT1receptor. The AT1receptor is in a constrained conformation and is activated only when bound to angiotensin II. In contrast, the AT2receptor is ‘relaxed’ in that no single interaction is critical for binding, like the N111G mutant AT1receptor, which is constitutively active.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThe effect on blood pressure of oral ‘replacement’ doses of exogenous oestrogen may depend on the type and dose of oestrogen administered. This study was designed to compare with placebo the effect of once daily treatment with a ‘natural’ oestrogen, piperazine oestrone sulphate, in two different doses and a semisynthetic oestrogen, ethinyloestradiol, on clinic and ambulatory blood pressure and the renin–angiotensin system in postmenopausal women.Design and methodsTwenty-four normotensive postmenopausal women (median age 54 years, range 47–60 years) participated in the study which used a double-blind crossover design. For each subject there were four randomized treatment phases, each lasting 4 weeks. The separate treatments administered once daily were 0.625 mg oestrone sulphate, 2.5 mg oestrone sulphate, 0.02 mg ethinyloestradiol and matching placebo. Clinic blood pressure, heart rate and weight were measured weekly with the mean values of weeks three and four of each phase used for analysis. Ambulatory blood pressure and biochemical measurements were performed in the final week of each phase.ResultsTwenty-four subjects entered and 22 completed the randomized phases of the study. Compared with the placebo phase, end-of-phase mean clinic diastolic blood pressure was reduced in subjects taking the semisynthetic oestrogen (P< 0.01) but was unchanged in those taking the ‘low’ and ‘high’ dose natural oestrogen. Mean clinic systolic blood pressure was also unchanged by any of the oestrogen treatments. Ambulatory night-time systolic, diastolic and mean arterial blood pressures were reduced with the low-dose natural and semisynthetic oestrogen treatments compared with placebo (P< 0.01), whereas there was no significant effect of the oestrogen treatments on ambulatory daytime blood pressures. A reduction in clinic and ambulatory heart rate was observed with the high-dose oestrone and semisynthetic oestrogen treatments. There was a dose-dependent increase in plasma renin substrate and decrease in plasma renin concentration with all active treatments; however, there was no change in plasma renin activity or plasma aldosterone concentration.ConclusionIn normotensive postmenopausal women, replacement doses of natural and semisynthetic oestrogen reduce night-time ambulatory blood pressure with either no change or a small reduction in clinic blood pressure. Reduction in blood pressure is not explained by reduced activity of the renin–angiotensin system but could have a component of reduced central sympathetic drive consistent with the decreased heart rate.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

BackgroundWe demonstrated in a previous cross-sectional study that arterial compliance is elevated in postmenopausal women taking estrogen-containing hormonal therapy, which may partially account for the reduction in cardiovascular risk observed.ObjectiveTo investigate the effects of withdrawal and recommencement of hormonal therapy, each for 4 weeks, on arterial compliance.MethodsSeventeen postmenopausal women [aged 56 ± 4 years (mean ± SD)] taking long-term hormonal therapy (+HT group) were studied at baseline, 4 weeks after withdrawal of hormonal therapy and again 4 weeks after recommencement. Systemic arterial compliance (SAC), pulse wave velocity (PWV) in the aorto-femoral and femoral-dorsalis pedis regions, and hemodynamic variables were measured at baseline, and at the end of each study intervention. As a time-control, seventeen postmenopausal women (aged 63 ± 7 years) not taking hormonal therapy (−HT group) were also investigated.ResultsSAC significantly decreased from 0.47 ± 0.06 to 0.40 ± 0.05 arbitrary compliance units (mean ± SEM;P< 0.05) after 4 weeks withdrawal from hormonal therapy. PWV in the femoral-dorsalis pedis region was elevated significantly by the withdrawal of hormonal therapy (8.4 ± 0.4 to 9.4 ± 0.5 m/s;P< 0.05), but PWV in the aortofemoral region did not change. After therapy had been recommenced for 4 weeks, SAC and PWV in the femoral-dorsalis pedis region were restored to baseline values. The −HT group showed no difference in SAC or PWV, and mean arterial pressure did not change in either group throughout the study period.ConclusionThese data suggest that hormonal modulation of distal arterial vascular tone may account for short-term changes in arterial compliance associated with estrogen-containing hormonal therapy.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo examine whether the increase of blood pressure in adrenocorticotrophin-treated rats is mediated through mineralocorticoid or glucocorticoid receptors or corticosterone 6β-hydroxylation inhibition.DesignRats were randomly allocated to 14 treatment groups for 10 days. The treatments included sham injection (n= 35), adrenocorticotrophin (5, 100, 500 μg/kg per day, subcutaneously,n= 5, 15 and 15, respectively), spironolactone (100 mg/kg per day, subcutaneously,n= 15), standard-dose or high-dose RU 486 (70 mg/kg every 3 days or 70 mg/kg per day, subcutaneously,n= 5 and 10, respectively), spironolactone + adrenocorticotrophin (100 μg/kg per day,n= 5, or 500 μg/kg per day,n= 10), standard-dose RU 486 + adrenocorticotrophin (500 μg/kg per day,n= 5), high-dose RU 486 + adrenocorticotrophin (100 μg/kg per day,n= 10), troleandomycin (40 mg/kg per day, subcutaneously,n= 5) and troleandomycin + adrenocorticotrophin (5 μg/kg per day,n= 5). Systolic blood pressure and metabolic parameters were measured every second day.ResultsAdrenocorticotrophin treatment increased systolic blood pressure dose-dependently (5 μg/kg per day: / 14 ± 2 mmHg; 100 μg/kg per day: +20 ± 2 mmHg; 500 μg/kg per day: +28 ± 2 mmHg, allP< 0.001). Adrenocorticotrophin at 100 and 500 μg/kg per day increased plasma sodium and decreased plasma potassium concentrations. Spironolactone did not block adrenocorticotrophin-induced systolic blood pressure changes but did block changes in plasma sodium and potassium levels. Standard-dose RU 486 did not modify the adrenocorticotrophin-induced (500 μg/kg per day) systolic blood pressure rise but blocked the effect of adrenocorticotrophin on body weight. High-dose RU 486 partially blocked the adrenocorticotrophin-induced (100 μg/kg per day) systolic blood pressure increase (adrenocorticotrophin at 100 μg/kg per day: 143 ± 3 mmHg; high-dose RU 486 + adrenocorticotrophin at 100 μg/kg per day: 128 ± 5 mmHg,P< 0.001) and body-weight loss. Troleandomycin did not alter the development of adrenocorticotrophin-induced hypertension.ConclusionsSpironolactone and standard-dose RU 486 did not modify adrenocorticotrophin-induced hypertension despite demonstrable antimineralocorticoid and antiglucocorticoid actions. High-dose RU 486 partially blocked adrenocorticotrophin-induced (100 μg/kg per day) hypertension, suggesting either a permissive effect of glucocorticoid on blood pressure or other antihypertensive actions of RU 486. Inhibition of glucocorticoid 6β-hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6β-hydroxylation in adrenocorticotrophin-induced hypertension are negligible.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100 240.DesignA randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers.MethodsMDL 100 240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n= 6) or 80 (n= 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate asp-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance.ResultsSupine systolic blood pressure was consistently decreased by MDL 100 240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high-and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100 240 (P< 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P= 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100 240 were good.ConclusionsThe increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100 240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveThe aim of this study was to evaluate the effect of trandolapril, an angiotensin converting enzyme inhibitor, on blood pressure, forearm blood flow and insulin sensitivity in comparison with nifedipine gastrointestinal therapeutic system.Patients and methodsThis is a multicentre, two-way parallel-group, open-label comparative study in 90 overweight hypertensive patients, who were randomly assigned to treatment for 8 weeks with either trandolapril or nifedipine. At baseline and after treatment, all patients underwent an oral glucose tolerance test, an evaluation of their metabolic profiles and a euglycaemic hyperinsulinaemic clamp test. In a subgroup of 18 patients, a forearm study was carried out.ResultsBlood pressure fell by the second week of treatment and remained significantly reduced compared with baseline in both treatment groups. Plasma triglyceride levels were also significantly reduced after trandolapril therapy, but no significant changes occurred in the other metabolic parameters during treatment with either drug. During the euglycaemic hyperinsulinaemic clamp, whole-body glucose use was similar in the two treatment groups at baseline, and a moderate but statistically significant increase in insulin sensitivity was observed after trandolapril treatment (trandolapril: 5.0 ± 0.2 versus 4.5 ± 0.2 mg/kg per min; nifedipine: 4.1 ± 0.3 versus 4.2 ± 0.3 mg/kg per min;P< 0.05, versus baseline and trandolapril versus nifedipine treatment). Skeletal muscle glucose uptake was significantly higher after trandolapril than after nifedipine therapy (5.0 ± 0.7 and 3.0 ± 0.4 mg/min, respectively;P< 0.01). As forearm blood flow was similar in the two treatment groups at baseline and was unchanged after 8 weeks of therapy, skeletal muscle glucose extraction was significantly greater in the ACE inhibitor treated-group than in the nifedipine comparative group (trandolapril: baseline 21 ± 2, treatment 24 ± 3 mg/dl; nifedipine: baseline 18 ± 3, treatment 16 ± 2 mg/dl;P< 0.05, trandolapril versus nifedipine treatment).ConclusionsDuring short-term treatment, ACE inhibition with trandolapril was able to moderately improve insulin sensitivity, in comparison with calcium blockade, and this effect appeared to be independent of the haemodynamic action of the drug.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectivePrevious studies have demonstrated that losartan can block the thromboxane A2receptor on the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation.MethodsPlatelets were obtained from 15 healthy men, aged 26–40 years. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by the thromboxane A2analog U46619 (5 × 10−6mol/l) or ADP (10−5mol/l).ResultsU46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-dependent manner. Only a high dose of EXP 3174 (5 × 10−5mol/l), thein vivoactive metabolite of losartan, was able to attenuate U46619-induced platelet activation. Captopril, an angiotensin I converting inhibitor, failed to modify U46619-induced platelet aggregation. Furthermore, the binding of [3H]-U46619 to platelets was competitively inhibited by losartan, whereas only a high dose of EXP 3174 reduced the binding of [3H]-U46619. Captopril failed to modify the binding of [3H]-U46619 to platelets. Losartan also reduced the platelet activation induced by ADP (10−5mol/l), a platelet agonist partially dependent on thromboxane A2. In addition, when thromboxane A2generation was blocked by aspirin, ADP-induced platelet aggregation was inhibited to a similar degree to the inhibition induced by losartan.Exogenous angiotensin II did not elicit any modification of either U46619- or ADP-stimulated platelet aggregation.ConclusionsLosartan decreased platelet aggregation by a thromboxane A2-dependent mechanism. EXP 3174 was less potent than losartan in reducing thromboxane A2-dependent platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced thromboxane A2-dependent platelet activation independently of its effect on angiotensin II.

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:1999

数据来源: OVID