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.     

Effect of ACE inhibition and angiotensin AT1 receptor blockade on renal and blood pressure response to L-arginine in humans

OBJECTIVE: Nitric oxide (NO) may contribute to the actions of angiotensin converting enzyme (ACE) inhibitors. In contrast, angiotensin type 1 (AT1) receptor blockers (AT1B) have been considered to act exclusively by inhibiting angiotensin II actions. However, recent experimental findings suggest that AT1B actions may be also partly mediated by NO. In this study, we explored whether ACE inhibitors and AT1B modulate hemodynamic responses to L-arginine (L-arg), a NO precursor. METHODS: Systemic (Finapres) and renal hemodynamic responses to L-arg (200 mg/kg body weight), associated with markers of systemic and renal NO production, were assessed before (control) and after 3 weeks of randomized pretreatment with the ACE inhibitor ramipril (5 mg/day for 3 weeks) or the AT1B losartan (50 mg/day for 3 weeks) in nine healthy male subjects (33 +/- 2 years; body mass index 25.5 +/- 0.5 kg/m2). RESULTS: Control L-arg did not influence mean arterial pressure (MAP) (92 +/- 5 versus 90 +/- 5 mmHg; not significant). In contrast, L-arg decreased MAP when administered after pretreatment with ramipril (89 +/- 5 versus 83 +/- 4 mmHg; P< 0.01) or losartan (90 +/- 44 versus 86 +/- 4; P< 0.05). Control L-arg infusion had no effect on renal plasma flow (RPF) (paraminohippuric acid clearance) and renal vascular resistance (RVR), whereas the glomerular filtration rate (GFR) (inulin clearance) decreased (98 +/- 4 versus 89 +/- 5 ml/min; P< 0.05), resulting in a decrease in filtration fraction (P< 0.05). After ramipril, L-arg induced renal vasodilation as indicated by significant changes in RPF (576 +/- 41 versus 669 +/- 21 ml/min; P< 0.01) and RVR (P< 0.05). The GFR did not change statistically after ramipril pretreatment (91 +/- 3 versus 97 +/- 4 ml/min; not significant); however, the trend was different as compared with control (F= 5.7, P < 0.05). L-Arg-induced renal vasodilation was also observed after losartan (RPF, 637 +/- 34 versus 706 +/- 40 ml/min; P< 0.05). Enhanced renal and systemic responses to L-arg after ACE inhibitor and AT1B were associated with a rise in plasma L-citrulline levels, which was greater than after control L-arg (P < 0.05). However, other indicators of NO activity such as plasma and urinary cyclic guanosine 3',5'-monophosphate, and nitrates, remained unchanged throughout all experiments. CONCLUSION: The results indicate that ACE inhibitors and AT1B have a potential to enhance L-arg-induced vasodilation both in systemic and renal vascular beds. However, these hemodynamic responses were not associated with convincing changes in indicators of systemic or renal NO activity, suggesting a contribution of NO-independent vasodilator mechanisms.     

Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance

Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.     

Differing effects of mineralocorticoid receptor-dependent and -independent potassium-sparing diuretics on fibrinolytic balance

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (P=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1+/-7.8 to 16.9+/-9.9 ng/mL at 9 am, P=0.019; from 7.6+/-5.4 to 11.5+/-7.3 ng/mL at 11 am, P=0.027; from 9.3+/-7.7 to 13.7+/-8.5 ng/mL for average of all time points, P=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0+/-23.4 to 16.7+/-19.0 ng/mL at 10 am, P=0.041; from 17.5+/-21.7 to 12.7+/-16.8 ng/mL at 11 am, P=0.043; from 20.3+/-22.6 to 16.6+/-19.7 ng/mL for average of all time points, P=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (P=0.014), hypertension (P=0.002), and PAI-1 response to HCTZ (P=0.019), with a trend for aldosterone (P=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.     

Endothelin receptor blockade improves endothelial function in atherosclerotic patients on angiotensin converting enzyme inhibition

OBJECTIVES: Endothelin-1 (ET-1) and angiotensin II may contribute to endothelial dysfunction, which is associated with increased risk of events in patients with coronary artery disease. The objective was to test whether dual ETA/ETB receptor antagonism improves endothelium-dependent vasodilatation (EDV) in atherosclerotic patients, also on treatment with angiotensin converting enzyme (ACE) inhibitor. DESIGN AND SETTING: EDV and endothelium-independent vasodilatation were determined in 37 patients with atherosclerosis during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. The patients were then randomized to treatment with ramipril 10 mg o.d. (n=21) or placebo (n=16) for 3 months in a double-blind fashion. RESULTS: Intra-arterial infusion of the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788 (both 10 nmol min(-1)) increased basal FBF by 42 +/- 4% (P <0.001) and enhanced EDV (P <0.001). Following 3 months ramipril treatment, ET receptor blockade still enhanced EDV. Acetylcholine 10 and 30 mg min(-1) increased FBF by 68 +/- 12 and 64 +/- 12 mL min(-1)/1000 mL before vs. 101 +/- 17 and 101 +/- 16 mL min(-1)/1000 mL following ET receptor blockade in the ramipril group (P <0.001). CONCLUSIONS: Dual ETA/ETB receptor blockade improves endothelial function and exerts direct vasodilator effects in patients with atherosclerosis, also on treatment with ramipril suggesting that ET receptor blockade may have important therapeutic effects when added to ACE inhibition in these patients.     

Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.     

Pulsatile stretch induces release of angiotensin II and oxidative stress in human endothelial cells: effects of ACE inhibition and AT1 receptor antagonism

Mechanical forces and the activation of the renin-angiotensin system (RAS) may alter the NO/O2(*-) balance, imparing endothelial nitric oxide (NO) availability. This study investigates the link between RAS and NO/O2(*-) balance in human aortic endothelial cells (HAEC) exposed to pulsatile stretch with and without ACE inhibitor quinaprilat or angiotensin II type 1 (AT(1)) receptor antagonist losartan. Pulsatile stretch increased Ang II levels and O2(*-) production, reducing NO release. RAS blockade with quinaprilat or losartan restored the balance between NO and O2(*-). These results provide a molecular basis for understanding the vascular protective effects of ACE inhibition and AT(1) receptor antagonism.     

Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase

BACKGROUND: Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT(1)-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. METHODS AND RESULTS: Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT(1)-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4+/-1.1 versus 3.8+/-0.9 and AT(1)-A, 13.5+/-1.0 versus 3.9+/-0.9 U. mL(-1). min(-1); each P<0.01). CONCLUSIONS-Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.     

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.     

Role of angiotensin II type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis

BACKGROUND: Inflammation is a central feature of coronary artery disease (CAD) that is characterized by increased expression of cellular adhesion molecules with the exception of L-selectin. L-selectin is a leukocyte adhesion molecule that is rapidly shed after leukocyte activation so that it appears to be decreased in CAD. The renin-angiotensin system (RAS) is implicated in atherogenesis and up-regulates these molecules. OBJECTIVES: The aim of this study was to investigate the effect of angiotensin type 1 (AT1) receptor antagonism on serum and leukocyte adhesion molecule expression in patients with CAD. Blood samples were collected from 31 patients before and after 8 weeks of treatment with losartan (44 +/- 2 mg/d, mean +/- SE), an AT1 receptor antagonist. We measured serum intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial-leukocyte adhesion molecule, and C-reactive protein (CRP). By flow cytometry, we also measured the expression of leukocyte CD11a, CD11b, CD11c, CD18, CD31, CD49d, and CD62L (L-selectin) in 13 patients. RESULTS: Treatment with losartan decreased systolic blood pressure (141 +/- 3 vs 135 +/- 4 mm Hg, P =.04) and increased plasma renin activity (1.2 +/- 0.4 vs 2.7 +/- 0.5 ng/mL/h, P =.001). There was a significant increase in L-selectin expression on monocytes (86 +/- 6 vs 118 +/- 10 MESF units, P =.007), lymphocytes (52 +/- 10 vs 79 +/- 8, P =.01), and granulocytes (124 +/- 7 vs 156 +/- 18, P =.056). However, there were no changes in the other leukocyte and serum adhesion molecules or CRP. CONCLUSIONS: These findings suggest that AT1 receptor antagonism selectively modulates L-selectin expression on leukocytes and that endogenous stimulation of AT1 receptors by the RAS contributes to the activation of leukocytes and decreased expression of L-selectin in CAD.     

Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene

We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate-salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the Ren-1 gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg. kg(-)(1). d(-)(1)) and an angiotensin type 1 (AT(1)) receptor antagonist (L-158809, 4 mg. kg(-)(1). d(-)(1)) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128+/-2 mm Hg) compared with controls (109+/-2 mm Hg) (P:<0.001), while plasma renin concentration was decreased by 97% (P:<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (P:<0.001). Urinary albumin (P:<0.05) and proliferating cell nucleic antigen-positive cells in the tubules and interstitium of the renal cortex (P:<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT(1) antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT(1) antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT(1) antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT(1) antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.     

Central vasopressin is modulated by chronic blockade of the renin-angiotensin system in experimental left ventricular hypertrophy

We studied the interaction of the central renin-angiotensin system (RAS) and vasopressin system in rats with left ventricular hypertrophy (LVH) due to aortic banding. In these animals plasma vasopressin is elevated and vasopressin content is increased in specific brain areas. Chronic blockade of the RAS by angiotensin-converting enzyme (ACE) inhibition (ramipril) and AT1 receptor antagonism (losartan) significantly attenuated circulating and central vasopressin in rats with LVH. Given the antidiuretic, vasoconstrictive, and growth-promoting effects, vasopressin may participate in the cardiovascular alterations in LVH. Blockade of the RAS strongly ameliorates central and peripheral-vasopressin. Therefore, central modulatory effects on vasopressin might contribute to the therapeutic efficacy of ACE inhibitors and AT1 antagonists.     

Angiotensin converting enzyme insertion/deletion polymorphism is associated with plasma antigen levels of plasminogen activator inhibitor-1 in healthy Japanese population.

Plasminogen activator inhibitor-1 (PAI-1) has a central role in the regulation of the fibrinolytic enzyme system. An elevated plasma PAI-1 level is associated with thrombotic disorders. In vitro and in vivo studies indicate that the renin-angiotensin system is involved in the regulation of PAI-1. A 287-bp insertion/deletion (I/D) polymorphism in the gene-encoding angiotensin converting enzyme (ACE) is associated with cardiovascular disorders. We evaluated the association between the ACE I/D polymorphism and plasma PAI-1 antigen levels in 110 healthy Japanese male subjects. Subjects with the D-allele of the gene-encoding ACE had higher levels of PAI-1 (26.3 +/- 14.7 ng/ml, mean +/- standard deviation) compared with those without (21.0 +/- 12.0; P = 0.0491). A multiple linear regression model with independent variables (age, body-mass index, total cholesterol level, triglyceride level, ACE I/D genotype, and PAI-1 genotype due to a single guanine I/D polymorphism in the PAI-1 gene) demonstrated that the triglyceride level (P = 0.0059) and ACE I/D genotype (P = 0.0372) were independent predictors of plasma PAI-1 antigen levels in a subset of the subjects without diabetes mellitus that were not taking lipid-lowering drugs. These findings suggest that the ACE I/D polymorphism is a genetic factor for the regulation of plasma PAI-1 antigen levels in the healthy Japanese population.     

Endogenous NO regulates plasminogen activator inhibitor-1 during angiotensin-converting enzyme inhibition

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.     

Chronic blockade of the angiotensin II receptor has a differential effect on adipose and vascular PAI-1 in OLETF rats

Angiotensinogen (AGT) and plasminogen activator inhibitor-1 (PAI-1) are expressed in both vascular and adipose tissues. Angiotensin II (AG II) has an adipogenic effect and increases PAI-1 expression. To evaluate the chronic effects of AG II type 1 receptor (AT(1)R) antagonism on adipose mass and PAI-1 expression in vascular and adipose tissues, losartan (30mg/kg/day) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes, for 20 weeks. Adipose mass and regional fat distribution in the abdomen did not change after chronic AT(1)R antagonism in OLETF rats. AGT and PAI-1 mRNA expressions in adipose tissue of OLETF rats were significantly increased compared with Long-Evans Tokushima Otsuka (LETO) rats, the normal control. Chronic losartan therapy further increased the level of adipose AGT in OLETF rats, but did not affect the level of adipose PAI-1 mRNA. In contrast, aortic PAI-1 expression in OLETF rats was attenuated by chronic losartan therapy. Our results have two implications. First, adipose tissue may be an important source of AG II in metabolic syndrome even after chronic losartan therapy. Second, chronic AT(1)R antagonism with losartan causes differential effects on vascular and adipose PAI-1 expression.     

Influence of the 4G/5G PAI-1 genotype on angiotensin II-stimulated human endothelial cells and in patients with hypertension

BACKGROUND: We examined the influence of the 4G/5G PAI-1 (plasminogen activator inhibitor) genotype on Angiotensin II (Ang II)-induced PAI-1 expression by human endothelial cells (HUVEC) in the presence and absence of AT1-receptor blocker losartan, and screened for this polymorphism in relation to plasma PAI-1 and arterial pressure in apparently healthy subjects. METHODS AND RESULTS: Genotyped cultured HUVEC were incubated with Ang II (10(-8) M) with or without losartan up to 24 h. PAI-1 mRNA was determined in cell extracts and protein and activity assessed in supernatants and extracellular matrix (ECM). Ang II increased PAI-1 mRNA and activity in a genotype-dependent manner, higher values observed for 4G/4G HUVEC compared with 4G/5G and 5G/5G genotypes (p<0.05). Laser confocal microscopy and Western blot analysis showed increased PAI-1 protein within ECM in Ang II-stimulated cultures. PAI-1 expression and protein secretion induced by Ang II in 4G/4G HUVEC was completely inhibited by preincubation with 0.05 microM losartan (p<0.01), indicating an AT1-mediated effect. In a group of hypertensives homozygous for the 4G allele, PAI-1 antigen was significantly increased (51.0+/-10.1 ng/ml) compared with normotensives (28.3+/-4.0 ng/ml) and hypertensives carrying the 5G allele (p<0.05). CONCLUSIONS: The 4G/5G PAI-1 polymorphism determines the endothelial PAI-1 upregulation by Ang II and the inhibitory response to losartan. Analysis of PAI-1 genotypes may help identifying subgroups of hypertensives at higher cardiovascular risk.     

AT_1受体拮抗剂及血管紧张素转换酶抑制剂对充血性心力衰竭纤溶活性影响的意义

目的 :研究服用血管紧张素转换酶抑制剂 (ACEI)培哚普利及 AT1 受体拮抗剂氯沙坦对充血性心力衰竭 (CHF)纤溶活性影响的意义及可能机制。方法 :采用随机单盲交叉方法 ,选择 30例 CHF患者不同日两次给予培哚普利 4m g及氯沙坦 5 0 m g治疗 ,并检测服药前基础状态及服药后 6 h血浆纤溶酶原激活物 (t- PA)活性、纤溶酶原激活物抑制物 (PAI- 1)活性、内皮素 - 1(ET- 1)及血管紧张素 (Ang )的含量。结果 :与治疗前比较 ,治疗后 t- PA浓度增加 ,PAI- 1、ET- 1、Ang 均降低。服用氯沙坦治疗前后结果比较差异有显著性意义 (P<0 .0 5 ) ;而服用培哚普利治疗前后比较差异无显著性意义 (P >0 .0 5 )。结论 :与 ACEI相比 ,服用 AT1 受体拮抗剂改善 CHF纤溶活性更明显 ,这种改变可能是通过改善内皮细胞功能 ,从而抑制 Ang 生成实现的。     

氯沙坦和依那普利对心肌梗死后纤溶-凝血功能的影响

目的　探讨氯沙坦和依那普利对急性心肌梗死 (AMI)患者纤溶 凝血功能的影响。方法　将 41例AMI患者随机分为氯沙坦组、依那普利组和对照组 ,以发色底物法和ELISA法测定三组患者入院即刻、发病 2周、2个月的血浆PAI 1活性、纤溶酶原激活物 (tPA)抗原水平和血管血友病病因子(vWF)含量。结果　与对照组相比 ,氯沙坦组 2周和 2个月时的PAI 1活性分别减低 2 2 % (P <0 0 1)和 18% (P <0 0 5 ) ,tPA抗原水平分别减低 32 % (P <0 0 1)和 2 5 % (P <0 0 5 ) ;依那普利组相应分别减低 2 8% (P <0 0 1)和 2 1% (P <0 0 5 ) ,tPA抗原水平分别减低 38% (P <0 0 1)和 2 9% (P <0 0 5 ) ;两个治疗组之间差异无显著性。两种药物对vWF含量均无影响。结论　氯沙坦和依那普利可改善心肌梗死后的纤溶功能 ,长期应用这两种药物可能会降低心肌梗死后发生急性心脏事件的危险。     

Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan

BACKGROUND: Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT(1)) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype-associated exertional LV growth and to clarify the role of the AT(1) receptor in this association. METHODS AND RESULTS: One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT(1) receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P:<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P:=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P:=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P:=0.0009). CONCLUSIONS: ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT(1) receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.