Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans.

Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT(1)) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT(1) antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5+/-1.8 years; mean body mass index 25.3+/-0.7 kg/m(2)) during low salt intake alone (10 mmol Na/d), low salt intake + quinapril (40 mg PO bid), and low salt intake + losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8+/-2.2 mm Hg), both quinapril (106.3+/-2.5 mm Hg, P<0.001) and losartan (105.4+/-2. 8 mm Hg, P<0.001) reduced BP. No statistical difference was found between quinapril and losartan in their BP lowering effect. Losartan (P=0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone (P<0.001 versus low salt alone for each); however, this effect was significantly greater for quinapril than for losartan (P<0.001 for quinapril versus losartan). Treatment with quinapril, but not with losartan, was associated with a decrease in both PAI-1 antigen (P=0.03) and activity (P=0.018). PAI-1 activity was lower during treatment with quinapril than with losartan (P=0.015). The average PAI-1 antigen concentration was 13. 0+/-2.0 ng/mL during low salt alone, 10.5+/-1.6 ng/mL during quinapril treatment, and 12.3+/-2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan (P=0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT(1) antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences.     

Effects of candesartan and lisinopril on the fibrinolytic system in hypertensive patients

The effects of the angiotensin II receptor blocker candesartan and the angiotensin-converting enzyme inhibitor lisinopril on the fibrinolytic system were investigated in a double-blinded, prospective, randomized study. Seventy-seven hypertensive patients taking candesartan (n=41) and lisinopril (n=36) with a systolic blood pressure >130 mm Hg and/or a diastolic blood pressure >80 mm Hg obtained by 24-hour ambulatory blood pressure measurement were included in the study. Blood pressure, plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the molar ratio of PAI-1/tPA were determined before treatment and 6 weeks later. Blood pressure decreased in both groups (candesartan, 155/85 mm Hg to 140/84 mm Hg; P<.05; lisinopril, 152/85 mm Hg to 138/83 mm Hg; P<.05). The fibrinolytic balance was significantly different between treatment groups (molar ratio of PAI-1/tPA: candesartan, 3.66 [2.2;] lisinopril, 5.44 [2.6;] P<.05). In contrast to lisinopril, the balance between coagulation and fibrinolytic activity shifted toward fibrinolysis during candesartan treatment.     

Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors

OBJECTIVES: The goal of this study was to determine: 1) whether bradykinin (BK) directly stimulates tissue plasminogen activator (tPA) secretion in human coronary circulation, and 2) whether angiotensin-converting enzyme (ACE) inhibition favorably alters the fibrinolytic balance regulated by BK. BACKGROUND: Bradykinin is a potent stimulator of tPA secretion in endothelial cells; however, the effect of BK on tPA release in the human coronary circulation has not been studied. METHODS: Fifty-six patients with atypical chest pain were randomly assigned to two groups: 25 patients were treated with the ACE inhibitor enalapril (ACE inhibitor group), and 31 were not treated with ACE inhibitors (non-ACE inhibitor group). Graded doses of BK (0.2, 0.6, 2.0 microg/min), acetylcholine (ACh) (30 microg/min) and papaverine (PA) (12 mg) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by Doppler flow velocity measurement. Blood samples were taken from the aorta (Ao) and the coronary sinus (CS). RESULTS: Bradykinin induced similar increases in CBF in both groups. The net tPA release induced by BK was dose-dependently increased in both groups, and the extent of that increase in the ACE inhibitor group was greater than that in the non-ACE inhibitor group. Bradykinin did not alter plasminogen activator inhibitor-1 (PAI-1) levels in the Ao or CS in either group. Neither ACh nor PA altered tPA levels or PAI-1 levels in either group. CONCLUSIONS: Intracoronary infusion of BK stimulates tPA release without causing any change in PAI-1 levels in the human coronary circulation. In addition, this effect of BK is augmented by an ACE inhibitor.     

Age-related effects of regular physical activity on hemostatic factors in men

Background Age-related changes in blood coagulation and fibrinolytic factors are associated with an increase in risk of thrombotic events. The purpose of this study was to assess the effects of age, regular aerobic exercise and detraining on blood coagulation and fibrinolytic factors in men. Methods Initially, 41 sedentary and 42 physically active men (20–64 years) were analyzed for plasma levels of coagulation and fibrinolytic factors. Twelve sedentary men were then subjected to 16-week aerobic exercise training and subsequent 2-week detraining. Their blood samples taken at rest were assayed for activity levels of prothrombin, coagulation factor (F) V, VII, VIII, IX, X, XI and XIII, antithrombin III, protein C and plasminogen, and for antigen levels of fibrinogen, prothrombin fragment 1 + 2 (F1 + 2), FIX, protein C, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and tPA/PAI-1 complex. Results Plasma levels of most coagulation factors, particularly for fibrinogen and FIX antigens as well as FXIII activity significantly increased with aging in sedentary men, while that tendency disappeared in physically active men. By the exercise training, plasma antigen and/or activity levels of most blood coagulation factors except for prothrombin and FIX decreased. These training-effects, however, disappeared after detraining, and in some cases even rebounded to higher levels than those of pre-training. Plasma antigen levels of tPA, PAI-1 and tPA/PAI-1 complex decreased with the training and remained low even after detraining. Conclusion Regular aerobic exercises give complex effects on expression of hemostatic factors, overall favoring the hemostatic balance to less thrombotic, partly cancelling out the age effects.     

Antihypertensive Drug Treatment and Fibrinolytic Function

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension—at least with diuretics and β-blockers—may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, β-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.     

Impact of antioxidants and HDL on glycated LDL-induced generation of fibrinolytic regulators from vascular endothelial cells

Hyperglycemia and dyslipoproteinemia are biochemical markers of diabetes mellitus (DM). Elevated levels of plasminogen activator inhibitor-1 (PAI-1) with and without reduction of tissue plasminogen activator (tPA) in plasma have been frequently found in patients with DM. Our previous studies indicated that glycation enhances low density lipoprotein (LDL)-induced production of PAI-1 and further decreases tPA generation in vascular endothelial cells (ECs). The present study demonstrated that treatment with antioxidants, butylated hydroxytoluene or vitamin E, blocked native LDL- and glycated LDL-induced changes in PAI-1 and tPA generation in ECs. Native or glycated high density lipoprotein (HDL) did not significantly alter tPA generation in ECs. Glycated but not native HDL (>/=100 microg/mL) moderately increased PAI-1 release from ECs. Cotreatment with native or glycated HDL inhibited LDL-induced or glycated LDL-induced changes in PAI-1 and tPA generation in ECs. The abundance of conjugated dienes was increased in glycated or EC-modified LDL. Treatment with butylated hydroxytoluene, vitamin E, or HDL reduced the abundance of conjugated dienes in glycated or EC-modified LDL. The effects of antioxidants and HDL on LDL-induced or its glycated LDL-induced changes in the generation of PAI-1 and tPA were also found in cultured human coronary artery ECs. The findings of the present study suggest that antioxidants and HDL may attenuate native LDL- or glycated LDL-induced changes in the generation of fibrinolytic regulators from vascular ECs, which possibly results from their inhibition on the lipid peroxidation of LDL particles. Treatment with antioxidants or hypolipidemic agents potentially improves fibrinolytic activity and reduces thrombotic tendencies in patients with DM.     

Markedly impaired fibrinolytic balance contributes to cardiovascular risk in adults with growth hormone deficiency

CONTEXT: Adults with GH deficiency (GHD) have multiple cardiovascular risk factors, including an unfavorable lipid profile and body composition as well as impairments in endothelial function and cardiac performance. We hypothesized that GHD is associated with elevated levels of plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of plasminogen activation in the circulation. OBJECTIVE: The objective of the study was to determine the fibrinolytic profile of adults with GHD in comparison with controls. STUDY DESIGN AND PARTICIPANTS: This was a prospective, observational study including 12 adults with GHD. Twelve gender-, age-, and body mass index-matched adults served as controls. MAIN OUTCOME MEASURES: The primary outcome measures were circadian plasma PAI-1 antigen with corresponding tissue-plasminogen activator (tPA) activity values. Endothelial function was assessed by flow-mediated vasodilation and fibrinolytic potential by venous occlusion test. RESULTS: Adults with GHD exhibited an unfavorable 24-h fibrinolytic profile characterized by a mean 62% elevation in PAI-1 antigen (2.77 ng/ml after adjustment for baseline PAI-1; P = 0.049) in the setting of a mean 24% reduction in tPA activity (-0.17 IU/ml after adjustment for baseline tPA; P = 0.003). Fibrinolytic response was defective in GHD, as demonstrated by a sustained elevation in PAI-1 activity greater than 4 IU/ml after venous occlusion [7.2 IU/ml (interquartile range 0.8-17.4); P = 0.018]. Endothelial function was impaired in GHD, as quantified by percent flow-mediated vasodilation over 120 sec [area under the curve 3.8 (interquartile range -2.4 to 7.9) vs. 12.8 (interquartile range 2.1-19.4); P = 0.043]. CONCLUSIONS: Adults with GHD demonstrate alterations in plasma fibrinolytic balance, including elevated levels of PAI-1 antigen with decreased tPA activity. These changes may contribute to the increased cardiovascular morbidity within this population.     

Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension.

BACKGROUND: Impaired fibrinolysis is associated with thromboembolic complications in hypertensive patients. It has been reported that cardiovascular morbidity and mortality rates are high even after lowering the elevated blood pressure with antihypertensive drugs. The aim of this study was to assess the effect of clinically used dosages of enalapril and nitrendipine on the fibrinolytic system. METHODS: Tissue plasminogen activator antigen (tPA) and tissue plasminogen activator inhibitor-1 (PAI-1) activity were measured in 20 normotensive male subjects and 46 male patients with mild essential hypertension divided into 2 groups (22 patients treated with 5 to 10 mg enalapril once a day and 24 treated with 5 to 10 mg nitrendipine once a day) before and 3 months after drug administration. Plasma renin activity and norepinephrine concentration were also measured. RESULTS: There were no significant differences in basal characteristics between the 2 hypertensive groups. In both hypertensive groups, blood pressure was significantly reduced to a similar level after drug treatment. In the 2 hypertensive groups, plasma renin activity significantly increased after drug treatment; however, there were no significant changes in norepinephrine concentration. Before drug treatment, the 2 hypertensive groups had significantly higher tPA and higher PAI-1 activity than the normotensive subjects. In the enalapril group, there was no significant change in tPA although PAI-1 activity significantly decreased after drug treatment. In the nitrendipine group, there was no significant change in tPA although PAI-1 activity significantly increased after drug treatment. CONCLUSION: Thus enalapril improved impaired fibrinolysis but nitrendipine further aggravated fibrinolysis in essential hypertension. Considering the effect of antihypertensive drugs on the fibrinolytic system, more effective and beneficial treatment of hypertensives, especially at a high risk for thrombus formation might be selected.     

Endothelium and endogenous fibrinolysis

Reduced activity of the endogenous fibrinolytic system contributes to intramural deposition of microthrombi in atherogenesis and to intraluminal deposition of thrombi leading to acute complications of atherosclerosis such as acute coronary syndromes. Endogenous fibrinolytic activity is predominantly regulated by the plasminogen activator inhibitor type 1 (PAI-1). Increased activity of PAI-1 leading to reduced endogenous fibrinolytic activity has been identified as an important independent risk factor for cardiovascular disease. Vascular endothelial cells form a barrier between the circulating blood with its dynamic balance between ongoing thrombosis and fibrinolysis and the subendothelial layers of the vascular wall with their prothrombotic activity. In addition, endothelial cells synthesize and secrete substantial amounts of plasminogen activators and their inhibitor PAI-1. Thus, endothelium plays an important role in the regulation of endogenous fibrinolysis. After describing the components of the endogenous fibrinolytic system and its interactions, this review focuses on the impact on endogenous fibrinolysis by the renin angiotensin system, the kallikrein kinin system, and type 2 diabetes mellitus. Investigations using transgenic and knock-out animal models--the results of which are also summarized--have improved our understanding of the interaction between endogenous fibrinolysis and endothelium. In each section of the review therapeutic implications and potentials are discussed.     

Circadian pattern of acute variceal bleeding among cirrhotic Egyptian patients

Background  Liver cirrhosis is the most common cause of portal hypertension which may end in serious bleeding from gastro-esophageal varices. Recent studies have demonstrated a daily pattern of acute upper gastrointestinal bleeding in patients with liver cirrhosis evidenced by one or two peaks throughout the day. Aim  The assessment of the circadian rhythm of acute variceal bleeding with the possible participation of circadian changes of the fibrinolytic parameters. Patients and methods  The study included 264 patients with liver cirrhosis and upper gastrointestinal bleeding in addition to 20 healthy subjects as a control group. A series of hemostatic tests and parameters including prothrombin (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), Factors II, V, VII, IX, X, XI, platelets counts and fibrinolytic parameters assessement were completed in 60 patients in addition to the control group. The fibrinolytic activity was assessed by estimation of plasminogen, tissue plasminogen activator antigen (tPA: Ag) and plasminogen activator inhibitor antigen (PAI-1: Ag) at hour 09:00 and hour 17:00. The hemostatic tests and liver function tests were assessed once at hour 09.00. Results  We observed statistically significant two time peaks of upper gastrointestinal bleeding at hour 04:00 and hour 17:00 with a peak of the fibrinolytic parameter, tissue plasminogen activator antigen, with the night peak of bleeding. A significant correlation between the levels of fibrinolytic parameters and hemostatic factors as well as liver function tests were detected. Conclusion  There are two time peaks of upper gastrointestinal bleeding with a temporal association between the night peak and a relative hyperfibrinolytic state.     

Antihypertensive drugs and fibrinolytic function

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.     

Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study

An impaired fibrinolytic function due to elevated plasma levels of plasminogen activator inhibitor (PAI)-1 activity or tissue plasminogen activator (tPA) antigen is correlated with the development of myocardial infarction (MI) in patients with manifest coronary heart disease. Recently, methods for determining the specific tPA/inhibitor complexes constituting tPA antigen in plasma have become available. In the Stockholm Heart Epidemiology Program (SHEEP) study, 86 of 1212 MI patients, subjected to blood sampling in a metabolically stable period, suffered reinfarction before the end of 1996. These individuals have been compared with an approximately equal number of matched MI patients without recurrence and a group of matched healthy control subjects regarding the plasma concentrations of some hemostatic factors. The hemostatic compounds studied (fibrinogen, von Willebrand factor, tPA antigen, PAI-1, and the tPA/PAI-1 complex) were typically higher in the groups (men and women) with recurrence of MI compared with those without. The plasma concentrations were also typically higher in the pooled groups of patients compared with the groups of healthy control subjects. The largest between-group differences were found for the plasma tPA/PAI-1 complex. The crude odds ratio for reinfarction associated with higher concentration (>/=75th percentile among the control subjects) of tPA/PAI-1 was 1.8 (95% CI 1.1 to 3.1); the corresponding crude odds ratio for von Willebrand factor was 2.3 (1. 3 to 4.0). The tPA/PAI-1 complex correlated strongly with PAI-1 and tPA antigen in all groups and with serum triglycerides and body mass index in all groups except for women with reinfarction. An increased plasma level of tPA/PAI-1 complex is a novel risk marker for recurrent MI in men and women. Most likely, increased plasma levels of tPA/PAI-1 complex reflect impaired fibrinolysis, because the correlation with PAI-1 is strong. Further support is obtained indicating that the plasma concentration of von Willebrand factor is also an important risk marker for recurrent MI.     

The Fibrinolytic System in Human Ascites

Background: We recently reported that the contact and kallikrein-kinin systems are activated in malignancy-related ascites. We have now studied the fibrinolytic system in ascites and plasma from patients with gastrointestinal cancer (n = 14) and nonmalignant liver disease (n = 18). Methods and Results: Enzyme immunoassays (EIAs) showed that urokinase and tissue plasminogen activators (uPA, tPA) and PA inhibitors (PAI-1, PAI-2) were present in ascites from both patient groups and that tPA was the predominant PA. uPA, tPA, and PAI-1, but not PAI-2, were detected in plasma from patients and controls. These EIA findings were supported by zymography studies. Functional assays showed considerable generation of plasmin-like activity and low plasminogen and antiplasmin values in malignancy-related ascites. The plasmin/antiplasmin and tPA/PAI-1 ratios were particularly high in malignancy-related ascites as compared with nonmalignant ascites. Plasma from the liver disease patients showed a higher tPA/PAI-1 ratio and, thus, a higher potential for plasminogen activation than plasma from cancer patients and controls. Patient plasma showed low values of plasmin-like activity, antiplasmin, and plasminogen. Conclusion: Our findings show that the fibrinolytic system is activated in malignancy-related ascites.     

Impact of diabetes-associated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells.

Increased thrombotic tendency and decreased fibrinolytic activity have been frequently found in patients with diabetes mellitus (DM). Previous studies by our group indicated that nonenzymatically glycated low density lipoprotein (LDL) increased plasminogen activator inhibitor-1 (PAI-1) production and decreased the generation of tissue plasminogen activator (tPA) from cultured human umbilical vein endothelial cells (HUVEC). The present study demonstrates that plasma levels of PAI-1 or PAI-1/tPA were significantly increased in patients with type 1 (n = 10) and type 2 DM (n = 14) compared with those in healthy controls (n = 10; P < 0.05 or 0.01). LDL from patients with type 1 or type 2 DM, and very low density lipoprotein (VLDL) from patients with type 2 DM induced significantly greater increases in the release of PAI-1 and more profound reduction in tPA generation from HUVEC compared with corresponding lipoproteins from healthy controls (P < 0.05 or 0.01). HDL from diabetic patients did not significantly alter the generation of PAI-1 or tPA from endothelial cells (EC) compared with HDL from controls. Comparable effects of lipoproteins from DM patients on the generation of PAI-1 and tPA were found in human coronary artery EC. LDL and VLDL from patients with type 2 DM enhanced the activation of PAI-1 promoter (-1528/+55)/luciferase reporter gene transiently transfected in HUVEC (P < 0.01). The results of the present study suggest that LDL and VLDL from patients with DM reduce the generation of tPA and increase PAI-1 production through the activation of the PAI-1 promoter in vascular EC.     

Angiotensin-converting enzyme insertion/deletion polymorphism modulates coronary release of tissue plasminogen activator in response to bradykinin.

The aim of this study was to assess the relationship between the angiotensin converting enzyme gene (ACE) genotype and endothelium-dependent coronary vasomotor and fibrinolytic activity. The ACE DD genotype has been reported to be a risk factor for myocardial infarction. However, the mechanism is unknown. The fibrinolytic and renin-angiotensin systems are linked via ACE at the vascular beds. We studied 73 patients (II: n=24; ID: n=37; DD: n=12) who underwent diagnostic cardiac catheterization. Graded doses of bradykinin (BK) (0.2, 0.6, 2.0 microg/min) and acetylcholine (30,100 microg/min) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by measuring Doppler flow velocity. Blood samples were taken from the aorta (Ao) and the coronary sinus (CS). Coronary release of tPA antigen was determined as a CS-Ao gradientXCBFX[(100-hematocrit) / 100]. ACE genotypes were determined using polymerase chain reaction. The ACE genotype did not appear to affect coronary macro- and microvascular responses induced by BK or acetylcholine. Coronary tissue plasminogen activator (tPA) release induced by BK was depressed in subjects with the ACE DD genotype. ACE levels in the DD genotype were significantly higher than those in the ID or II genotype. In all of the subjects, there was a significant negative correlation between the serum level of ACE activity and net coronary tPA release in response to BK at 0.6 microg/min. In conclusions, the DD genotype of the ACE gene impairs the coronary release of tPA induced by BK.     

Effects of lisinopril, irbesartan, and amlodipine on the thrombogenic variables in the early and late stages of the treatment in hypertensive patients

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.     

氯沙坦和阿替洛尔对高血压患者纤溶系统及血浆血管性血友病因子的作用比较

目的比较血管紧张素受体拮抗剂(ARB)氯沙坦和β受体阻滞剂阿替洛尔对原发性高血压患者纤溶系统及血浆血管性血友病因子(vWF)的影响。方法轻中度原发性高血压患者60例随机分成氯沙坦组和阿替洛尔组(每组30例),分别给予氯沙坦50mg/(次.d)或阿替洛尔50mg/(次.d),共治疗8周。每4周随访1次,4周时血压如不达标(BP<140/90mmHg)则加用双氢克尿噻12.5mg/(次.d)。治疗前后行血浆组织型纤溶酶原激活物(tPA)及纤溶酶原激活物抑制剂1(PAI-1)检测,并计算PAI-1/tPA作为纤溶参数,同时测定血浆vWF的含量。结果两组的基线血压等一般情况具有可比性。治疗4周及8周时两组血压均较治疗前显著下降,组间比较无差异。同治疗前相比,氯沙坦组治疗8周时血浆PAI-1和vWF水平下降(P值分别<0.05及<0.01),PAI-1/tPA也有显著下降(P<0.05),而tPA则无显著变化(P>0.05);阿替洛尔组治疗8周时血浆PAI-1和vWF水平及PAI-1/tPA均无显著变化,而tPA则有所上升(P<0.05)。治疗后血浆vWF两组间比较,差异有非常显著意义。结论氯沙坦治疗能改善原发性高血压患者的纤溶系统并降低血浆vWF,而阿替洛尔则未见有此作用。     

ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension

BACKGROUND: Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with an increased incidence of myocardial infarction. Recent studies have investigated a potential influence of ACE gene polymorphism on fibrinolysis or endothelial function. It has been previously established that essential hypertension is accompanied by endothelial dysfunction and fibrinolytic balance disorders. The aim of our study was to study the relation between ACE gene polymorphism and fibrinolytic/hemostatic factors as well as endothelial cell damage markers in patients with hypertension. METHODS: The following parameters were evaluated in 104 patients with previously untreated hypertension: plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) antigen, fibrinogen, D-dimer, and von Willebrand factor (vWF). The genotype of the ACE gene was also determined (by the polymerase chain reaction method), and patients were characterized according to the observed alleles as deletion/deletion (DD), insertion/insertion (II), or insertion/deletion (ID). RESULTS: Those with DD genotype (n = 42) had significantly higher plasma levels of PAI-1 antigen (P =. 012), tPA antigen (P =.0001), fibrinogen (P =.0002), D-dimer (P =. 0001) and vWF (P =.0004) compared with ID (n = 30) or II (n = 32) genotypes. The ACE gene genotypes appeared to be significant predictors for plasma PAI-1 antigen, tPA antigen, fibrinogen, D -dimer, and vWF even after adjustment for age, sex, body mass index, triglyceride and cholesterol levels, and blood pressure. CONCLUSIONS: Our findings suggest that the ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial damage in patients with untreated hypertension.     

Circadian fluctuations of tissue plasminogen activator antigen and plasminogen activator inhibitor-1 antigens in vasospastic angina.

To elucidate the circadian variation of fibrinolytic components in vasospastic angina, plasma levels of tissue plasminogen activator antigen (t-PA), free plasminogen activator inhibitor antigen (free PAI-1), t-PA/PAI-1 complex, and total PAI-1 were measured in venous plasma samples. Samples were taken every 6 hours (6:00 AM, noon, 6:00 PM, and midnight) for 24 hours in 14 patients with vasospastic angina, in 9 patients with exertional angina, and in 19 normal subjects. Twenty-four-hour Holter monitoring (Holter monitor, Del Mar Avionics, Irvine, Calif.) was also carried out in all subjects. All of the fibrinolytic components showed circadian variation, with a peak level at 6:00 AM in every study group except for the t-PA/PAI-1 complex in the group of patients with exertional angina. The values for all or the fibrinolytic components at each sampling time were higher in patients with coronary artery disease than in normal subjects. In particular, the mean value of free PAI-1 at 6:00 AM in patients with vasospastic angina was significantly higher than that in normal subjects and that in patients with exertional angina. This value of free PAI-1 in patients with vasospastic angina was closely associated with the duration of ischemic attacks. These results suggested that the circadian fluctuation of fibrinolytic components may be an important factor that leads to coronary thrombosis at the time of coronary spasm, especially in the early morning.