Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
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PMID:Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. 788 1

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.
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PMID:The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. 1067 14

ACE inhibition reduces plasminogen activator inhibitor-1 (PAI-1), a risk factor for myocardial infarction, whereas the effect of angiotensin receptor antagonism on PAI-1 is uncertain. The present study compares the time course of effects of ACE inhibition and angiotensin type 1 (AT1) receptor antagonism on morning plasma PAI-1 antigen. Blood pressure and endocrine, metabolic, and fibrinolytic variables were measured in 20 insulin-resistant (defined by fasting glucose >8.3 mmol/L, body mass index >28 kg/m2, or fasting serum triglyceride > or =2.8 mmol/L) hypertensive subjects (mean age, 47.9+/-2.1 years) (1) before and after 1 week of hydrochlorothiazide 12.5 mg/d, and (2) before and 1, 3, 4, and 6 weeks after addition of ramipril (escalated to 10 mg/d) or losartan (escalated to 100 mg/d). Hydrochlorothiazide decreased systolic (P=0.011) and diastolic (P=0.019) pressure. Ramipril (from 133.6+/-5.1/94.5+/-2.4 to 127.0+/-3.1/91.4+/-3.3 mm Hg) or losartan (from 137.0+/-3.9/93.1+/-2.9 to 123.7+/-2.6/86.4+/-2.1 mm Hg) further reduced systolic (P=0.009) and diastolic (P=0.037) pressure. The pressure effects of the 2 drugs were similar. Hydrochlorothiazide increased plasma PAI-1 (P=0.013) but not tissue-type plasminogen activator (tPA) (P=0.431) antigen. Addition of either ramipril or losartan significantly decreased plasma PAI-1 antigen (P=0.046). However, the effect of losartan on PAI-1 antigen was not sustained throughout the 6-week treatment period, such that there was a significant drugxtime interaction (P=0.043). tPA antigen decreased during either ramipril or losartan (P=0.032), but tPA activity decreased only during losartan (P=0.018). Short-term interruption of the renin-angiotensin-aldosterone system by either ACE inhibition or AT1 receptor antagonism decreases PAI-1 antigen, but the duration of this effect is greater for ACE inhibition than for AT1 receptor antagonism.
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PMID:ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. 1246 70

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

Impaired fibrinolytic function, characterized by increased plasminogen activator inhibitor type 1 (PAI-1) levels and decreased tissue plasminogen activator (t-PA) activity, has been found in patients with hypertension and may account in part for the increased risk of atherosclerosis and its clinical complications in these patients. Failure to correct this prothrombotic state may be one of the possible reasons for the disappointing effect of antihypertensive treatment on the incidence of coronary events. In this regard, data from the literature indicate that different antihypertensive drugs may vary in their influence on fibrinolysis. Scarce and conflicting data exist regarding the effects of diuretics and beta-blockers on the fibrinolytic system. Angiotensin-converting enzyme (ACE) inhibitors (ACE-I) have generally been shown to improve the fibrinolytic balance by reducing plasma PAI-1 levels, calcium channel blockers (CCB) have been reported to increase t-PA activity, and angiotensin receptor blockers (ARB) seem to be neutral in their effect. Interesting data have been reported about the positive impact on fibrinolysis of combining an ACE-I with a CCB, which resulted in a decrease of PAI-1 caused by ACE inhibition, and an increase in t-PA resulting from calcium channel blockade. The positive effect of ACE-I on the fibrinolytic system has been related to: 1) inhibition of angiotensin II, which stimulates PAI-1 expression; 2) inhibition of degradation of bradykinin, a potent stimulus for tPA production; and 3) improvement of insulin sensitivity. The mechanisms underlying the CCB effect on t-PA are less clear, but a direct action of CCB on vascular endothelium has been reported to play a major role. The greater improvement in the fibrinolytic balance because of the combined action of ACE inhibition and Ca antagonism represents a further indication to the use of combinations of ACE-I and CCB in the treatment of hypertension.
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PMID:Antihypertensive drugs and fibrinolytic function. 1716 77

Regulation of the fibrinolytic balance between plasminogen activators and inhibitors is modulated by the renin-angiotensin system (RAS). Impaired fibrinolytic function, characterized by increased plasminogen activator inhibitor type 1 (PAI-1) levels and decreased tissue plasminogen activator (t-PA) activity, has been found in patients with hypertension and may account in part for the increased risk of atherosclerosis and its clinical complications in these patients. In this regard, data from the literature indicate that different antihypertensive drugs may vary in their influence on fibrinolysis. Angiotensin-converting enzyme (ACE) inhibitors (ACE-I) have generally been shown to improve the fibrinolytic balance by reducing plasma PAI-1 levels. Calcium-channel blockers (CCB) have been reported to increase t-PA activity, and angiotensin receptor blockers (ARB) seem to be neutral in their effect. In the light of these data, this study aimed to compare the effects of ACE-I, ARB, and CCB on the fibrinolytic system in the early and late stages of the treatment in hypertensive patients. These data that the beneficial effect of RAS inhibition on fibrinolysis related to decrease in Ang II during early period of treatment. Amlodipine may also improve thrombogenic risk related to lowering the effect on increased platelet activation reflected by p-selectin. The greater improvement in the early and late stages of the fibrinolytic balance because of the combined action of RAS inhibition and Ca antagonism represents a further indication to the use of combinations of RAS inhibition (ACE-I or ARB) and CCB in the treatment of hypertension.
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PMID:Effects of lisinopril, irbesartan, and amlodipine on the thrombogenic variables in the early and late stages of the treatment in hypertensive patients. 2196 26