摘要:

ObjectivesTo examine the long-term effects of the angiotensin type I (AT1) receptor antagonist, valsartan, on fibrinolytic balance, coagulation parameters, endothelial function and structural alterations in atherosclerotic rabbits.MethodsAnimals were submitted to a 1% cholesterol-enriched diet for 10 weeks. Half of the animals were treated with valsartan (3 or 10 mg/kg per day). Systolic arterial pressure was directly measured in awake rabbits. Tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI-1) activities were measured. Plasma concentrations of cholesterol, D-dimer, factor VIII and fibrinogen, as well as thrombin time, were also determined. Responses to acetylcholine, sodium nitroprusside and angiotensin II were evaluated in aortic rings. Morphometric analysis of aortic segments was also performed to calculate atherosclerotic lesion.ResultsCholesterol-fed rabbits presented systolic arterial pressure levels comparable to controls. These animals presented aortic atherosclerotic lesions. Treatment with valsartan did not alter plasma cholesterol levels or arterial pressure in any group. Acetylcholine-induced relaxations and D-dimer and t-PA activity were lower (P<0.05) in atherosclerotic than in normal rabbits. In contrast, PAI-1 activity was higher (P<0.05) in atherosclerotic rabbits than in controls. Valsartan increased (P<0.05) acetylcholine-induced relaxations, D-dimer concentration and t-PA activity, and reduced intimal thickening and PAI-1 activity in cholesterol-fed rabbits. Fibrinogen concentrations and factor VIII concentrations were lower (P<0.05) and thrombin time was higher (P<0.05) in atherosclerotic rabbits compared to controls. Valsartan did not affect factor VIII in any group, but reduced fibrinogen levels only in hypercholesterolemic rabbits. Valsartan 10 mg/kg per day reduced (P<0.05) thrombin time in cholesterol-fed rabbits.ConclusionsImpairment of fibrinolytic balance, associated with atherosclerosis in rabbits, appears to be related with angiotensin II via AT1receptors. The beneficial effect of valsartan on fibrinolysis seems to be related to the concomitant amelioration of endothelial dysfunction and reduction of intimal thickening, further supporting the importance of the blockade of angiotensin II actions to prevent thrombotic alterations associated with atherosclerosis.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesIncreasingly, studies indicate that alterations in leukocyte and endothelial cell adhesion molecules may enhance atherosclerotic processes in human hypertension. β-adrenergic receptor activation has long been implicated in the aetiology and/or maintenance of hypertension and also has significant effects on leukocyte and endothelial adhesion molecules. This study therefore examined the effects of hypertension on peripheral blood mononuclear cell CD62L and CD11a expression and circulating soluble interstitial cell adhesion molecule (ICAM)-1 (sCD54) levels following infusion of the non-specific β-adrenergic agonist isoproterenol.DesignIn the setting of a General Clinical Research Center, 15 hypertensive and 20 normotensive subjects underwent an infusion of isoproterenol consisting of two sequential 15 min fixed-order doses of 20 and 40 ng/kg per min. Flow cytometry was used to quantify lymphocyte and monocyte populations and adhesion molecules, and ELISA was used to quantify sCD54 levels.ResultsAs expected, isoproterenol led to a significant increase in the number of circulating lymphocytes (P<0.001) and monocytes (P<0.01). The number of circulating CD3+CD8+CD62LlowT cytotoxic cells increased following isoproterenol (P<0.001) and this increase was greater in hypertensives than in normotensives (P<0.05). Isoproterenol led to a decrease in surface density of CD62L (P<0.001) and an increase in surface density of CD11a (P<0.001) in all subjects. Hypertensives had a significantly lower CD62L density (P= 0.01) and higher CD11a density on lymphocytes (P= 0.002) compared to normotensives. sCD54 levels were unchanged following isoproterenol but were elevated in hypertensives (P<0.05).ConclusionsA β-adrenergic-induced environment of increased CD62Llow/CD11ahighleukocytes, coupled with existing endothelial CD54 activation, could support basic atherosclerotic processes of increased peripheral blood mononuclear cell–endothelial adhesion in hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveThe present study was designed to determine the effects of prolonged treatment with cilnidipine, a novel dihydropyridine calcium antagonist which blocks both L-type and N-type calcium channels, on systemic, regional and coronary hemodynamics, cardiovascular mass and collagen content in normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats.MethodsMale 23-week-old WKY and SHR rats were divided into two groups for each strain. One group received cilnidipine (10 mg/kg per day), whereas their respective controls were given no therapy. Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic mass, and hydroxyproline concentration were determined after 12 weeks treatment.ResultsThe data demonstrated that cilnidipine neither affected systemic hemodynamics nor cardiovascular mass and collagen content in WKY rats. The same treatment in the SHR reduced arterial pressure and total peripheral resistance without changes in heart rate and cardiac index. Ventricular and aortic mass indices as well as ventricular collagen content remained unchanged. There were no differences in organ blood flows between two SHR groups, whereas renal, liver and left ventricular coronary vascular resistances were reduced by cilnidipine. After dipyridamole infusion left ventricular minimal coronary vascular resistance decreased further in cilnidipine-treated SHR as compared with control SHR rats.ConclusionThese data suggest that cilnidipine, an L- and N- type calcium channel antagonist, exerted beneficial effects on coronary hemodynamics without altering cardiovascular mass or collagen content in SHR.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo determine whether combinations of metabolic risk factors (obesity, diabetes and hypercholesterolemia) influence the magnitude of left ventricular (LV) mass and prevalence of LV hypertrophy.DesignCross-sectional, relational.MethodsA total of 1627 hypertensive (85.9% treated, 1036 women, 1041 African Americans) and 342 normotensive (180 women, 183 African Americans) participants in theHypertensionGeneticEpidemiologyNetwork (HyperGEN) Study, without prevalent cardiovascular disease, were studied. Echocardiographic LV mass, normalized by height2.7or fat-free mass or body surface area (BSA) and the ratio of stroke volume to pulse pressure as a percentage of predicted (as a crude estimate of arterial compliance) were analyzed in relation to obesity [by body mass index (BMI)], central fat distribution (by waist circumference), diabetes (by ADA criteria) and hypercholesterolemia.ResultsObesity, hypercholesterolemia, and diabetes were more frequent among hypertensives than normotensives (allP<0.001). After controlling for age, sex, race and type and combination of antihypertensive medication, LV mass/height2.7, but not LV mass/fat-free mass and LV mass/BSA, increased with the number of metabolic risk factors, both in normotensive and hypertensive participants, also after further adjustment for blood pressure (allP<0.001). Stroke volume/pulse pressure also decreased in hypertensive, but much less in normotensive subjects, with increasing number of metabolic risk factors, independently of relevant confounders (P<0.0001). Prevalence of LV hypertrophy was predicted by older age, hypertension, central fat distribution, black race and independently increased with the number of associated metabolic risk factors (P<0.0001).ConclusionsThe progressive addition of metabolic risk factors including central obesity, diabetes and hypercholesterolemia is associated with higher LV mass normalized by height2.7, independently of hypertension and other important biological covariates. Obesity played a major role in this association. This finding indicates that LV mass is a potentially useful bioassay of strategies of global cardiovascular prevention.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveIn this randomized, double-blind, crossover study, the antihypertensive efficacy of amlodipine and nifedipine gastrointestinal therapeutic system (GITS) was compared following missed doses.Design and methodsIn a randomized crossover design, 42 patients were randomized to receive amlodipine (5–10 mg) or the GITS formulation of nifedipine (nifedipine GITS) (30–60 mg) once daily for 12 weeks, thenvice versa. During weeks 8, 10 and 12 of each treatment period, compliance failures were simulated by patients missing 0, 1 or 2 doses of their medication, and ambulatory systolic (SBP) and diastolic (DBP) blood pressure measurements were obtained.ResultsFollowing steady-state treatment (i.e. ‘perfect compliance'), there was no difference between amlodipine and nifedipine GITS in SBP (140.1 versus 134.2 mmHg) or DBP (84.0 versus 85.8 mmHg) at 0–24 h post-dose. When compliance was not perfect, i.e. when one or two doses were missed, DBP was maintained at a significantly lower level with amlodipine compared with nifedipine GITS at 24–48 h post-dose (83.1 versus 86.4 mmHg,P= 0.005) and at 48–72 h post-dose (84.2 versus 89.7 mmHg,P<0.001). Plasma concentrations of amlodipine were better maintained than those of nifedipine GITS. At 72 h post-dose, the plasma concentration of amlodipine was 61% (17.0±11.2 ng/ml) compared with<25% (28.3±49.9 ng/ml) for nifedipine GITS.ConclusionDuring short periods of non-compliance, antihypertensive efficacy remains more predictable with amlodipine than with nifedipine GITS.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo investigate the reasons for withdrawal from double-blind randomized trials, and the reasons for changing treatment within a randomized therapeutic group.DesignThe Syst-Eur trial, in which 4695 older patients with systolic hypertension were randomized to active or placebo treatment.MethodsThe reasons for withdrawal from the trial were examined, both for patient-initiated and investigator-initiated withdrawals. In addition, the reasons for stopping the first-line treatment (nitrendipine), the second-line treatments (enalapril and hydrochlorothiazide) and the corresponding placebos, were determined.ResultsA total of 135 patients (6%) were withdrawn by the investigators from placebo treatment because their blood pressure was too high, and, similarly, 36 (1.6%) through patient initiation. The corresponding results for the actively treated patients were 14 (0.6%) and 7 (0.3%). Very few patients were withdrawn from the trial because of the adverse effects of treatment. However, 39 (4%) stopped taking active nitrendipine because of ankle oedema, compared with 4 (0.5%) on placebo. Similarly, 28 versus three stopped due to flushing. Forty-one (10%) stopped taking enalapril because of cough, against eight (2%) for enalapril placebo. In all, 15.0% stopped active nitrendipine, 20.2% enalapril and 6.3% hydrochlorothiazide, versus placebo 7.1, 9.1 and 5.1%.ConclusionsThe numbers withdrawn from the trial for adverse treatment consequences were small in comparison to the cardiovascular benefits. Nevertheless the numbers stopping individual treatments were higher than expected.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID