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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities in fibrinolysis have been reported in hypertension. Angiotensin converting enzyme (ACE) inhibitors have been shown to improve altered fibrinolytic balance in hypertensive patients. It has not been documented, however, whether this is due to a decrease in angiotensin II (Ang-II) generation or is a consequence of elevated local levels of bradykinin. Accordingly, the aim of this study was to determine the effects of an ACE inhibitor (perindopril) and an Ang-II receptor antagonist (losartan) on fibrinolytic kinetics. We have examined the serum levels of the plasminogen activator inhibitor type-1 (PAI-1) antigen and activity, tissue plasminogen activator (t-PA) antigen and activity, soluble thrombomodulin (sTM), and tissue factor pathway inhibitor (TFPI) before and after reaching the target blood pressure (<140/90 mm Hg) in 13 hypertensive patients receiving perindopril (mean age 40+/-11 years, 6 women, 7 men) and in 12 patients receiving losartan (mean age 38+/-9 years, 6 women, 6 men). We also compared the baseline fibrinolytic activity of hypertensive patients with that of 12 normotensive control persons (mean age 40+/-9 years, 6 women, 6 men). The mean basal plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were significantly higher in the hypertensive patients than in normal controls (P<.005). The values of other analytes were similar in both groups. Increased plasma levels of PAI-1 antigen, PAI-1 activity, and sTM were reduced in patients after they were given perindopril and losartan (P<.005); the reductions in losartan-receiving group were more pronounced (P<.05). There were no significant effects on the plasma levels of t-PA antigen, t-PA activity, and TFPI in patients receiving the two therapeutic regimens (P>.05). In conclusion, chronic hypertension is associated with hypofibrinolysis. The beneficial effect of ACE inhibitors on fibrinolysis seems to be related to the blockade of Ang-II, and increased kinin activity does not appear to play a major role.
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PMID:Effects of angiotensin converting enzyme and angiotensin II receptor inhibition on impaired fibrinolysis in systemic hypertension. 1060 82

Systemic gene therapy involves the transfer into the body of a gene whose protein product reaches the blood and has a beneficial effect on a patient. Both retroviral and adenovirus-associated viral vectors have resulted in stable but only moderate systemic levels of blood proteins. Adenoviral vectors have resulted in very high levels of expression that diminishes over days or weeks. Hepatic gene therapy has achieved levels of the anticoagulant protein C in blood that would protect against spontaneous thromboses in homozygous protein-C deficiency, and levels of tissue plasminogen activator that can lyse pulmonary emboli. Hypercholesterolemia has been ameliorated transiently by transfer of the low-density lipoprotein receptor gene into the livers of animals with familial hypercholesterolemia or by promoting lipid transfer via a variety of alternative mechanisms. Hypertension has been reduced by the transfer of genes for kallikrein or atrial natriuretic peptide into the liver, or by expressing antisense for the angiotensin II type I receptor after intravenous injection in neonates. Finally, fasting but not fed hyperglycemia has been ameliorated in animal models of diabetes by transfer of an insulin gene into the liver or by expression of insulin from implanted fibroblasts. Gene therapy has the potential to treat these cardiovascular diseases. However, improvements in levels of long-term expression and the ability to regulate expression in response to physiologic changes will be required before this approach will be implemented for most of these disorders in humans.
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PMID:Systemic gene therapy for cardiovascular disease. 1063 21

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been associated with increased risk for myocardial infarction, cardiomyopathy, carotid thickening, and cardiac hypertrophy. However, a conclusive agreement about the role of ACE genotype in the genetics of cardiovascular disease has not yet been reached. This study was undertaken to investigate the relationship of the I/D polymorphism of the ACE gene with carotid intima-media thickness (IMT) and left ventricular mass (LVM) in 175 Chinese patients with mild-to-moderate hypertension. The I/D genotypes were detected by the polymerase chain reaction using primers flanking the polymorphic region in intron 16 of the ACE gene. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. Patients with the DD genotype (n = 41) showed significant greater carotid IMT (1.593 +/- 0.879 v 1.309 +/- 0.703 and 1.171 +/- 0.583 mm, P = .01) but insignificant higher LVM index (123.8 +/- 36.6 v 123.7 +/- 37.4 and 118.2 +/- 33.0 g/m2, P = .61) than did those with the DI (n = 69) and II (n = 65) genotypes. The deletion polymorphism of the ACE gene (P = .04) was a significant predictor for carotid IMT on multiple regression analysis, controlling all the potential confounding factors including age (P = .001), systolic blood pressure (P = .09), smoking (P = .08), and plasma tissue plasminogen activator antigen (P = .03), but the LVM correlated only with age (P = .02), sex (P < .001), and body mass index (P < .001). These results indicated that the DD genotype of the ACE gene could be considered a risk factor for the development of early atherosclerosis in carotid arteries but not for left ventricular hypertrophy in the hypertensive population.
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PMID:Carotid thickening, cardiac hypertrophy, and angiotensin converting enzyme gene polymorphism in patients with hypertension. 1067 81

Subjects with type 2 diabetes have markedly increased rates of coronary heart disease (CHD) that are only partly explained by the increased levels of conventional cardiovascular risk factors such as total cholesterol, hypertension, and smoking. Although an increasing number of studies have suggested a role for glycemia in cardiovascular disease, considerable controversy remains. This issue may be resolved when the results of the UK Prospective Diabetes Study (UKPDS) are presented. One possible promising relatively new risk factor that may explain high levels of CHD in diabetic subjects is increased oxidative stress. Type 2 diabetic subjects have an increased preponderance of small dense low-density lipoprotein (LDL), which predisposes to the oxidation of LDL. Almost all studies show that diabetic subjects have increased oxidative stress. In addition, they may have lower levels of alpha-tocopherol. In most studies, increased oxidative stress has been associated with cardiovascular disease, although prospective data are lacking. If levels of oxidative stress are increased, what are the best levels to reduce it to? Improved glycemic control has been associated with decreased oxidative stress. Antioxidant replacement such as alpha-tocopherol may also be beneficial. Interestingly, some special properties of hypoglycemic agents have been described. Gliclazide has been reported to favorably affect both free radicals and platelet reactivity. Gliclazide may have a more favorable effect on tissue plasminogen activator (tPA) than tolbutamide. In conclusion, increased levels of oxidative stress may underlie some of the increased risk of cardiovascular disease in diabetic subjects. Interventions to decrease levels of oxidative stress by methods such as improved glycemic control, antioxidant therapy (ie, alpha-tocopherol), and gliclazide are indicated.
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PMID:Clinical relevance of the oxidative stress concept. 1069 18

We recently discovered that patients with essential hypertension have a markedly impaired capacity for stimulated release of tissue plasminogen activator (tPA) from vascular endothelium. This defect may reduce the chance of timely spontaneous thrombolysis in case of an atherothrombotic event. We now investigated whether increased intraluminal pressure as such may depress vascular tPA release or downregulate its gene expression. Segments of human umbilical veins were studied in a new computerized vascular perfusion model under steady laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear stress (10 dyne/cm(2)). Quantitative immunohistochemical evaluation of cellular tPA immunoreactivity was performed on paraffin-embedded 5-microm vascular sections. tPA mRNA in endothelial cells was quantified with reverse transcription real-time TaqMan polymerase chain reaction with GAPDH as endogenous control. Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western blotting, followed by densitometric quantification. High-pressure perfusion downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (P=0.01) compared with vessels perfused under normal intraluminal pressure. tPA release into the perfusion medium was markedly suppressed by high pressure (P<0.01 ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3 hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein expression and inhibits its release from the endothelium independently of shear stress. The defective capacity for stimulated tPA release that we demonstrated in patients with essential hypertension might thus be an effect of the elevated intraluminal pressure per se.
Hypertension 2000 Apr
PMID:Elevated intraluminal pressure inhibits vascular tissue plasminogen activator secretion and downregulates its gene expression. 1077 76

The stroke consensus dating from 1991 had to be revised, because of the introduction of new developments in the treatment of patients with stroke. More than 50 representatives from 25 professions and institutions participated. Under methodological assistance of the Dutch Institute for Healthcare Improvement CBO separate working groups (diagnosis, treatment, organization of care, rehabilitation/education, implementation and cost-effectiveness) studied the literature and translated the results into recommendations with explanatory text. The strength of scientific evidence was classified. During a national public meeting the results were discussed. In the field of guideline development cost-effectiveness analyses and specific attention for implementation are new. Care on a stroke unit decreases the risk of mortality, life-long disabilities, and dependence on permanent care with about 20%. Regional stroke services should be instituted, in which continuity and efficient care can be guaranteed. Very early thrombolysis with recombinant tissue plasminogen activator strongly decreases the number of patients dying, or remaining care-dependent in a selected group of appropriate patients. Secondary prevention (lifestyle measures, acetylsalicyclic acid, treatment of hypertension and hypercholesterolaemia, and surgery of the carotids) may decrease the number of residual strokes and myocardial infarctions. In the occurrence of cerebral ischaemia and atrial fibrillation oral anticoagulants are indicated. Early intensive rehabilitation increases the chance of recovery. Silent cognitive defects may hinder rehabilitation. The extensive guideline summarises the scientific literature about treatment of patients with stroke and should serve as a basis for local protocols and appointments.
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PMID:[CBO guideline 'Stroke' (revision) Dutch Institute for Healthcare Improvement]. 1085 Jan 8

Hemostasis factors may influence the pathophysiology of stroke. The role of brain hemostasis in ischemic hypertensive brain injury is not known. We studied ischemic injury in spontaneously hypertensive rats in relation to cerebrovascular fibrin deposition and activity of different hemostasis factors in brain microcirculation. In spontaneously hypertensive rats subjected to transient middle cerebral artery occlusion versus normotensive Wistar-Kyoto (W-K) rats, infarct and edema volumes were increased by 6.1-fold (P < 0.001) and 5.8-fold (P < 0.001), respectively, the cerebral blood flow (CBF) reduced during middle cerebral artery occlusion (MCAO) by 55% (P < 0.01), motor neurologic score increased by 6.9-fold (P < 0.01), and cerebrovascular fibrin deposition increased by 6.8-fold (P < 0.01). Under basal conditions, brain capillary protein C activation and tissue plasminogen activator activity were reduced in spontaneously hypertensive rats compared with Wistar-Kyoto rats by 11.8-fold (P < 0.001) and 5.1-fold (P < 0.001), respectively, and the plasminogen activator inhibitor-1 antigen and tissue factor activity were increased by 154-fold (P < 0.00001) and 74% (P < 0.01), respectively. We suggest that hypertension reduces antithrombotic mechanisms in brain microcirculation, which may enhance cerebrovascular fibrin deposition and microvascular obstructions during transient focal cerebral ischemia, which results in greater neuronal injury.
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PMID:Brain injury and cerebrovascular fibrin deposition correlate with reduced antithrombotic brain capillary functions in a hypertensive stroke model. 1089 83

Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.
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PMID:Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study. 1099 95

Sixteen Japanese patients of both sexes aged 46-78 years with essential hypertension were studied at the cardiac clinic of the Department of Cardiology, Shizuoka General Hospital, Shizuoka, Japan. Serum lipids, lipoproteins, plasma fibrinolytic parameters, renin and noradrenaline were determined before and after 3 months of cilnidipine treatment. Systolic and diastolic blood pressures and heart rate were reduced while renin and noradrenaline levels remained unchanged after cilnidipine treatment. Total cholesterol and tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complex were reduced. Changes in the other lipids, lipoproteins and fibrinolytic parameters were not significant after cilnidipine treatment. A negative correlation was found between low-density lipoprotein cholesterol and t-PA antigen levels after cilnidipine treatment. In conclusion, cilnidipine was effective for the treatment of hypertension and did not cause reflex tachycardia in Japanese patients. Cilnidipine treatment produced a beneficial lipid profile (decrease in total cholesterol), but did not show a consistent effect on fibrinolytic parameters in hypertensive patients. The metabolic interaction between beneficial lipid changes and fibrinolysis will be of value to better our understanding of the antiatherogenic effects of cilnidipine treatment in hypertensive patients.
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PMID:Effects of cilnidipine on lipids, lipoproteins and fibrinolytic system in hypertensive patients. 1110 11

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.
Hypertension 2001 Mar
PMID:Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells. 1124 25


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