Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of obtaining insight in the structure/function relationship in the serpin plasminogen activator inhibitor type-1 can be understood from the major role PAI-1 plays in different (patho)physiological processes, mainly because of its involvement in the plasminogen/plasmin system. Moreover, during the past years, studies indicated a contribution of PAI-1 to the development of cardiovascular disease in common syndromes such as atherosclerosis, diabetes and hypertension. Furthermore, PAI-1 also inhibits u-PA, attributing a role in phenomena such as cell migration and tissue remodelling. Considering the role of PAI-1 in such various pathogenic path-ways, detailed insight into the structure/function relationship in PAI-1 might provide a means of interfering with a given pathological situation without disturbing other physiological processes. Therefore, since the discovery of PAI-1 and the cloning of its cDNA 20 years ago, over 600 PAI-1 variants have been constructed, elucidating the most important structural features of PAI-1. This review gives an overview of the contribution of the different PAI-1 variants to the understanding of the structure/function relationship in PAI-1, based on the different functional features of PAI-1.
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PMID:The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant? 1554 16

The increased prevalence of type 2 diabetes parallels the increased prevalence of obesity. Abdominal obesity contributes to insulin resistance. To overcome the insulin resistance, the pancreas makes more insulin, keeping the glucose in the normal range. Eventually, the pancreas will fail, resulting in elevated levels of blood glucose. Thus, to develop type 2 diabetes, an individual must have a defect in insulin sensitivity with an accompanying defect in insulin secretion. In the early stages of the disease, glucose can be controlled with appropriate therapeutic lifestyle changes aimed at lowering insulin resistance. As the disease progresses, one has to use medications. Insulin secretagogues increase insulin levels, whereas insulin sensitizers, such as metformin and thiazolidinediones, decrease insulin resistance. The defect in insulin secretion is progressive, and eventually, almost every patient needs exogenous insulin, which may be delayed with appropriate lifestyle changes. Insulin resistance is associated with a clustering of metabolic abnormalities called the insulin-resistance syndrome, which is a component of the metabolic syndrome. Insulin-resistance syndrome includes obesity, hypertension, dyslipidemia, and elevated levels of plasminogen activator inhibitor type 1. These abnormalities increase the risk of cardiovascular disease. Of people with type 2 diabetes, 70% die from premature cardiovascular disease. Prevention of the complications of diabetes requires good control of not only blood glucose but also other manifestations of the insulin-resistance syndrome, including hypertension and lipid abnormalities.
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PMID:Epidemiology of diabetes and obesity in the United States. 1564 25

Statins have pleiotrophic effects related to the pathogenesis of atherosclerosis and thrombogenicity of the vessel wall beyond lipid lowering. The aim of the present study was to examine the effect of atorvastatin treatment on the fibrinolytic system in patients with dyslipidemia. The investigation was carried out on 41 dyslipidemic patients (21 males and 20 females) with a mean age of 53.8 years (range, 30-76). The patients were divided into subgroups according to their cholesterol and triglyceride levels as hypercholesterolemic (n = 26) and mixed-type hyperlipidemic (n = 15) and their risk factors for coronary heart disease including age, sex, hypertension, obesity, smoking, and family history. The patients were started on atorvastatin 10 mg/day, and evaluated within 6-12 weeks to assess the changes in fibrinolytic parameters including global fibrinolytic capacity, plasminogen activator inhibitor type-1 and tissue plasminogen activator, and lipids. After successful lipid-lowering therapy, global fibrinolytic capacity (P = 0.003) and tissue plasminogen activator levels (P = 0.04) were found to be increased and plasminogen activator inhibitor type-1 levels (P = 0.02) decreased in dyslipidemic patients. Global fibrinolytic capacity levels increased (P < 0.001) and plasminogen activator inhibitor type-1 levels decreased (P = 0.01) in patients with hypercholesterolemia (n = 26). However, no significant changes were observed in fibrinolytic parameters in patients with mixed-type hyperlipidemia (n = 15). When the patients were separately evaluated according to risk factors, significant beneficial effects on the fibrinolytic system were observed, especially in patients without obesity and hypertension as well as in older patients and males. These findings suggest that atorvastatin treatment has a beneficial effect on the fibrinolytic system in patients with hypercholesterolemia, but not in patients with mixed-type hyperlipidemia. Further studies are needed to show whether higher doses and longer periods of lipid lowering treatment have beneficial effects in patients with mixed type hyperlipidemia and some risk factors.
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PMID:The effects of atorvastatin treatment on the fibrinolytic system in dyslipidemic patients. 1565 73

Due to excessive salt and water retention, hypertension often becomes refractory in patients undergoing peritoneal dialysis (PD). Management of high blood pressure (BP) appears to be of particular importance in such patients because of its substantial impact on the patients' prognosis. However, attempts to control hypertension in PD patients have not been successful in most cases. In this regard, the present study aimed to address the adequacy of current antihypertensive therapy for PD patients. A new antihypertensive strategy expected to improve the outcome was tested on the assumption that treatment with either angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) in the evening together with alpha1-blocker at bed time and long-acting Ca channel blocker (CCB) in the morning might ameliorate BP control associated with morning hypertension. Enrolled in the present study were 40 patients whose BP was evaluated by both office and home measurement. Due to an emerging concern about morning hypertension, home BP measured early in the morning was used for the analysis. Each patient was categorized into the following four groups in accordance with office and home BP: well-controlled, poorly-controlled, white-coat and masked (opposite to white-coat), hypertension. After the observation period, 28 patients with refractory hypertension were allocated to intensive antihypertensive therapy in which ARB or ACE-I previously prescribed in the morning or daytime was shifted to the night. In addition, alpha1-blocker was given at bed time. Furthermore, long-acting CCB and diuretics were shifted to the morning. The patients were then followed up for 4-6 months. The results were as follows: 1) Of the total number of 40 PD patients, systolic hypertension was noted in 50% of cases by office BP and in 80% by home BP. The former was less frequent than the latter (p=0.0047, n=40). Similarly, diastolic hypertension was noted in 20% by office BP and in 45% by home BP. The former was less frequent than the latter (p=0.0045, n=40 by McNemar's analysis). The distribution of BP control categories was well-controlled in 11%, poorly-controlled in 42%, masked hypertension in 39% and white-coat hypertension in 8% when determined by systolic BP. The distribution was well-controlled in 45%, poorly-controlled in 13%, masked hypertension in 34% and white-coat hypertension in 8% of cases when determined by diastolic BP. 2) In 28 patients subjected to the intensive therapy, the control category of systolic BP was changed from 11 to 37% in well-controlled cases, from 42 to 30% in poorly-controlled cases, from 39 to 26% in masked hypertension cases and from 8 to 7% in white-coat hypertension cases. The shift in categories in both poorly-controlled and masked hypertension cases to the better category (well-controlled), was statistically significant (p=0.001, by Wilcoxon's signed rank test). Similarly, the control category of diastolic BP was changed from 45 to 43% in well-controlled cases, from 13 to 15% in poorly-controlled cases, from 34 to 32% in masked hypertension cases and from 8 to 10% in white-coat hypertension cases. There was a tendency for the prevalence of poorly-controlled and masked hypertension to improve to the well-controlled category in response to intensive therapy (p=0.0625, by Wilcoxon's signed rank test). 3) The plasma concentration of plasminogen activator inhibitor (PAI-1)/tissue plasminogen activator (t-PA) complex (total PAI-1 complex) was significantly decreased after intensive therapy (17.3+/-7.8 ng/ml vs. 13.5+/-4.6 ng/ml, n=28, p<0.01 by paired t-test). In contrast, the plasma concentration of t-PA was unchanged even after intensive therapy (4.8+/-3.9 ng/ml vs. 6.2+/-2.9 ng/ml, n=28, ns). These data suggest that home BP obtained in the morning is a useful measure for evaluating morning hypertension in PD patients, most of whom have refractory hypertension categorized as either poorly-controlled or masked hypertension. Intensive treatment with ACE-I/ARB given in the evening along with alpha1-blocker at bed time combined with a diuretic and/or long-acting CCB in the morning is efficacious in controlling the BP of patients with refractory hypertension in PD patients. The link between the reduction in plasma total PAI-1 levels and the intensive therapy may suggest that this therapeutic strategy could prevent thrombotic events associated with morning hypertension in patients on PD.
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PMID:[Antihypertensive therapy for refractory morning hypertension in patients on peritoneal dialysis]. 1575 62

Hypertension is associated with decreased fibrinolytic potential, mainly expressed as elevated plasma plasminogen activator inhibitor type 1 (PAI-1) levels, and increased platelet aggregability, which may account in part for the increased risk of atherosclerosis and its clinical complications in hypertensive patients. The effects of antihypertensive drugs on this prothrombotic state have been investigated and controversial findings have been reported, possibly because of differences in study designs, patients selected, and methodology used. Scarce and conflicting data exist about the effects of diuretics and beta-adrenoceptor antagonists on the fibrinolytic system, whereas ACE inhibitors have generally been reported to improve the fibrinolytic balance by decreasing plasma PAI-1 levels, calcium channel antagonists have been shown to increase tissue plasminogen activator (tPA) activity, and angiotensin II type 1 (AT(1)) receptor antagonists seem to exert neutral effects. beta-Adrenoceptor antagonists, calcium channel antagonists, and AT(1)-receptor antagonists have been reported to exert anti-aggregatory effects on platelets, while contrasting data exist about the influence of ACE inhibitors. Clinical implications of the changes induced by antihypertensive drugs on the fibrinolytic balance and platelet function are still debated. In particular, the question of whether these changes may translate into different degrees of cardiovascular protection in hypertensive patients remains unanswered. While awaiting more information from clinical trials, the choice of antihypertensive drugs, particularly in high-risk patients, should take into account effects beyond their BP-lowering efficacy. Selected agents should have a favorable, or at least neutral, impact on fibrinolytic function and platelet activity.
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PMID:Is the effect of antihypertensive drugs on platelet aggregability and fibrinolysis clinically relevant? 1598 4

The existence of an association between idiopathic intracranial hypertension (IIH) and coagulation disorders in men was assessed prospectively. Microthrombi, associated with thrombophilia-hypofibrinolysis, occlude arachnoid sinus villi, thus reducing resorption of cerebrospinal fluid, leading to IIH. Ten consecutively referred men with IIH, nine whites, one African American, median age 36 years, were 2 to 1 matched by age and race by healthy male controls. Polymerase chain reaction assays were done for four thrombophilic and one hypofibrinolytic gene mutations: G1691A factor V Leiden, G20210A prothrombin, C677T MTHFR, platelet glycoprotein IIb/IIIa (PL A1/A2), and 4G/5G polymorphism of the plasminogen activator inhibitor (PAI-1) gene promoter. Coagulation measures in plasma included dilute Russel's viper venom time (dRVVT), activated partial thromboplastin time (aPTT), the lupus anticoagulant, factor VIII, factor XI, plasminogen activator inhibitor activity (PAI-Fx), protein C antigenic, protein S total (antigenic), protein S free (antigenic), antithrombin III (functional), and resistance to activated protein C (RAPC). Tests performed on serum included anticardiolipin antibodies, homocysteine, and Lp(a). The body mass index was 40 kg/m(2) or greater (extremely obese) in two men, 30 to 40 kg/m(2) (obese) in three, and was 25 to 30 kg/m(2) in five (overweight). Cases differed from controls for inherited 4G4G homozygosity of the PAI-1 gene, four of 10 (40%) vs. one of 20 (5%), Fisher's p [p(f)]= .031, and for high levels (>21.1 U/mL) of the hypofibrinolytic PAI-1 gene product, PAI-Fx, 5 of 10 (50%) vs. one of 18 (6%), p(f) = .013. Thrombophilic factor VIII was high (> or = 150%) in three of 10 (30%) cases vs. zero of 16 (0%) controls, p(f)=. 046. The thrombophilic lupus anticoagulant was present in two of 10 (20%) cases vs. zero of 32 (0%) controls, p(f) = .052. Heritable hypofibrinolysis and heritable and acquired thrombophilia appear, speculatively, to be treatable etiologies of IIH in men. Understanding contributions of hypofibrinolysis and thrombophilia to the development of IIH should facilitate development of novel new approaches to treat this often-disabling neurologic disorder.
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PMID:Idiopathic intracranial hypertension: associations with thrombophilia and hypofibrinolysis in men. 1624 70

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.
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PMID:Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure. 1636 59

Abdominal fat accumulation has been shown to play crucial roles in the development of metabolic syndrome. Visceral fat accumulation particularly is closely correlated to the development of cardiovascular disease and obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension. Given these clinical findings, the functions of adipocytes have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that secrete various bioactive substances termed adipocytokines. Among adipocytokines, tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. In contrast to these adipocytokines, adiponectin, which is an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor-necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin-binding epidermal growth factor-like growth factor, and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, particularly adiponectin, is discussed with respect to cardiovascular diseases.
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PMID:Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. 1639 16

To test the hypothesis that NO contributes to effects of angiotensin-converting enzyme inhibitors on fibrinolysis, fibrinolytic balance was assessed in 17 normal subjects during placebo and after randomized, double-blind 4-week treatment with the NO precursor L-arginine (3 g TID), ramipril (10 mg QD), or L-arginine+ramipril. Neither L-arginine nor ramipril alone affected basal plasminogen activator inhibitor-1 or tissue-type plasminogen activator (t-PA) antigen in these salt-replete subjects in whom plasma renin activity was suppressed (mean+/-SD 0.7+/-0.5 ng angiotensin I/mL per hour). In contrast, L-arginine+ramipril reduced morning plasminogen activator inhibitor-1 antigen (10.8+/-9.5 ng/mL) and the molar ratio of plasminogen activator inhibitor-1:t-PA (2.3+/-1.6) compared with placebo (13.5+/-10.8 ng/mL, P=0.006; ratio 2.9+/-2.1, P=0.015) or ramipril alone (15.2+/-13.2 ng/mL, P=0.009; ratio 3.7+/-3.3, P=0.005). L-arginine and ramipril synergistically increased d-dimers (23.1+/-31.5, 29.7+/-50.0, 35.1+/-50.0, and 57.1+/-144.8 ng/mL during placebo, L-arginine, ramipril, and L-arginine+ramipril, respectively; P<0.05 for L-arginine+ramipril versus any other group). During ramipril, the NO synthase inhibitor L-NG-nitro-arginine-methyl-ester (2 mg/kg) significantly increased plasminogen activator inhibitor-antigen after 2 hours (from 9.4+/-8.6 ng/mL during vehicle to 13.5+/-11.0 ng/mL during L-NG-nitro-arginine-methyl-ester; P=0.020), consistent with an effect on expression but rapidly increased t-PA activity (from 0.4+/-0.3 to 0.5+/-0.4 IU/mL; P=0.031), consistent with an effect on release. Both effects of L-NG-nitro-arginine-methyl-ester were reversed by L-arginine. During angiotensin-converting enzyme inhibition, endogenous NO decreases plasminogen activator inhibitor-1 antigen and improves fibrinolytic balance in normotensive salt-replete subjects.
Hypertension 2006 Mar
PMID:Endogenous NO regulates plasminogen activator inhibitor-1 during angiotensin-converting enzyme inhibition. 1643 54

Obstructive sleep apnea (OSA) is a common medical condition that occurs in a considerable percentage of the population. Substantial evidence shows that patients with OSA have an increased incidence of hypertension compared with individuals without OSA, and that OSA is a risk factor for the development of hypertension. It is established that OSA may be implicated in stroke and transient ischemic attacks. OSA is associated with coronary heart disease, heart failure, and cardiac arrhythmias. Pulmonary hypertension may be associated with OSA, especially in patients with pre-existing pulmonary disease. Although the exact cause that links OSA with cardiovascular disease is unknown, there is evidence that OSA is associated with a group of proinflammatory and prothrombotic factors that have been identified as important in the development of atherosclerosis. OSA is associated with increased daytime and nocturnal sympathetic activity. Autonomic abnormalities seen in patients with OSA include increased resting heart rate, decreased R-R interval variability, and increased blood pressure variability. Both atherosclerosis and OSA are associated with endothelial dysfunction, increased C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor, and reduced fibrinolytic activity. OSA has been associated with enhanced platelet activity and aggregation. Leukocyte adhesion and accumulation on endothelial cells are common in both OSA and atherosclerosis. Clinicians should be aware that OSA may be a risk factor for the development of cardiovascular disease.
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PMID:Inflammatory aspects of sleep apnea and their cardiovascular consequences. 1646 39


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