Beneficial effect of combined spironolactone and quinapril treatment on thrombosis and hemostasis in 2K1C hypertensive rats.

A strong correlation between raised aldosterone levels and increased risk of thrombotic disorders has been provided. Clinical studies have demonstrated the benefits of the addition of the aldosterone receptor antagonist to the standard therapy with angiotensin-converting enzyme inhibitor in the reduction of cardiovascular events in patients. We suggest that the benefits of this dual renin-angiotensin-aldosterone system (RAAS) blockade may be related to the drug's effects on the hemostatic and oxidative balance. Thus, we investigated the effect of combined spironolactone (SPIRO) and quinapril (QUIN) administration on thrombosis, hemostasis and oxidative stress in hypertensive rats. A two-kidney, one-clip model of renovascular hypertension in Wistar rats was used. QUIN, SPIRO, or QUIN + SPIRO were administered for 10 days. Venous thrombosis was induced by vena cava ligation. Thrombus weight and incidences of thrombosis were assessed. Bleeding time, platelet adhesion, tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thrombin activatable fibrynolysis inhibitor (TAFI), malonyl dialdehyde, and hydrogen peroxide plasma levels were assayed. Aortic expression of NADPH oxidase and superoxidase dismutase were measured. We observed significant RAAS activation associated with hypercoagulability and oxidative stress augmentation in renovascular hypertensive rats. Thrombosis was reduced only in rats treated with QUIN + SPIRO. In all groups, decreases in TF, PAI-1, and TAFI levels were observed, however in the QUIN + SPIRO group those changes were more pronounced. The inhibition of platelet adhesion was also stronger in rats treated with QUIN + SPIRO. The oxidative stress parameters were markedly reduced in rats treated with QUIN or SPIRO, although the most evident changes were observed in the QUIN + SPIRO group. Dual RAAS blockade with aldosterone receptor antagonist and angiotensin-converting enzyme inhibitor provides additional benefits for experimental thrombosis associated with the antiplatelet, anticoagulative, profibrinolytic, and antioxidative effects in renovascular hypertensive rats.

A novel electrochemiluminescence sensor coupled with capillary electrophoresis for simultaneous determination of quinapril hydrochloride and its metabolite quinaprilat hydrochloride in human plasma.

A novel electrochemiluminescence (ECL) sensor with composite consisted of silica-sol, Zinc oxide nanoparticles (ZnO NPs), polyvinylpyrrolidone (PVP) and tris(2, 2'-bipyridine) ruthenium (II) was constructed. A new method for simultaneous determination of quinapril hydrochloride (QHCl) and its metabolite quinaprilat hydrochloride (QTHCl) in human plasma was developed using the ECL sensor coupled with capillary electrophoresis (CE). ECL intensities of QHCl and QTHCl increased dramatically when the ECL sensor was used as working electrode. The running buffer contains 14mmol/L phosphate (pH 8.0) and 20% n-propyl alcohol. Under optimized experimental conditions, the linearity ranges of the method are 0.007-8.0µg/mL for QHCl and 0.009-8.3µg/mL for QTHCl. The detection limits of QHCl and QTHCl (S/N=3) are 3.6ng/mL and 3.9ng/mL, respectively. The method was applied for the simultaneous determination of QHCl and QTHCl in human plasma with satisfactory results.

ß-blocker Therapy is Not Associated with Reductions in Angina or Cardiovascular Events After Coronary Artery Bypass Graft Surgery: Insights from the IMAGINE Trial.

PURPOSE: To evaluate whether ß-blockers were associated with a reduction in cardiovascular events or angina after Coronary Artery Bypass Graft (CABG) surgery, in otherwise stable low-risk patients during a mid-term follow-up. METHODS: We performed a post-hoc analysis of the IMAGINE (Ischemia Management with Accupril post-bypass Graft via Inhibition of angiotensin coNverting Enzyme) trial, which tested the effect of Quinapril in 2553 hemodynamically stable patients with left ventricular ejection fraction (LVEF) >40 %, after scheduled CABG. The association between ß-blocker therapy and the incidence of cardiovascular events (death, cardiac arrest, myocardial infarction, revascularizations, angina requiring hospitalization, stroke or hospitalization for heart failure) or angina that was documented to be due to underlying ischemia was tested with Cox regression and propensity adjusted analyses. RESULTS: In total, 1709 patients (76.5 %) were using a ß-blocker. Patients had excellent control of risk factors; with mean systolic blood pressure being 121 ± 14 mmHg, mean LDL cholesterol of 2.8 mmol/l, 59% of patients received statins and 92% of patients received antiplatelet therapy. During a median follow-up of 33 months, ß-blocker therapy was not associated with a reduction in cardiovascular events (hazard ratio 0.97; 95 % confidence interval 0.74-1.27), documented angina (hazard ratio 0.85; 95 % confidence interval 0.61-1.19) or any of the individual components of the combined endpoint. There were no relevant interactions for demographics, comorbidities or surgical characteristics. Propensity matched and time-dependent analyses revealed similar results. CONCLUSIONS: ß-blocker therapy after CABG is not associated with reductions in angina or cardiovascular events in low-risk patients with preserved LVEF, and may not be systematically indicated in such patients.

Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors.

A series of novel 2-butyl-4-chloro-1-methylimidazole derived peptidomimetics were designed, synthesized and evaluated for their Angiotensin Converting Enzyme (ACE) inhibitor activity. 2-Butyl-4-chloro-1-methylimidazole-5-carboxylic acid 2 obtained after oxidation of respective carboxaldehyde 1, was condensed with various amino acid methyl esters 3a-k to give imidazole-amino acid conjugates 4a-k in very good yields. Ester hydrolysis of 4a-k with aqueous LiOH gave the desired peptidomimetics 5a-k. Screening all the new compounds 4a-k and 5a-k using ACE inhibition assay, resulted five compounds 4i, 4k, 5e, 5h and 5i as potent ACE inhibitors with IC50 of 0.647, 0.531, 1.12, 0.657 and 0.100µM with minimal toxicity. Among them, 5i emerged as most active ACE inhibitor with greater potency than marketed drugs Lisinopril, Ramipril and relatively equipotent to Benazepril, Quinapril and Enalapril.

A calcified left ventricular mass.

Mitral annular calcification is a degenerative process. It is mostly asymptomatic. As the calcification becomes more extensive it might be mistaken for an intracardiac tumour. Mitral annular calcification predicts cardiovascular events, cardiovascular death and overall death. It is predictive of a doubling of the stroke risk. Extensive mitral annular calcification may undergo liquefaction. Surgery is seldom needed.

Role of the angiotensin converting enzyme 1/angiotensin II/angiotensin receptor 1 axis in interstitial collagenase expression in human carotid atheroma.

BACKGROUND AND AIM: Angiotensin II (AII) receptor 1 (ATR1) and angiotensin converting enzyme 1 (ACE1) blockers have been shown to reduce acute cardiovascular events in patients, improve plaque stability and modify matrix metalloproteinase (MMP) expression. However, the role of the ACE1/AII/ATR1 axis in interstitial collagenase regulation has not been fully explored. In this study, we investigated the effect of ATR1 and ACE1 blockade on the expression and activity of MMP-1, -8 and -13 in human carotid atheroma. METHODS: Atheroma samples (n = 24) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ACE1 (quinapril), ACE2 (DX600) and MMP (GM6001) blockade on the expression of AII, the interstitial collagenases and soluble elastin fragments were investigated in explant culture supernatants. Paired atheroma samples were incubated with intervention or media control for 4 days. Protein levels (AII, MMP-1, -8, -13 and soluble elastin) were determined by ELISA. RESULTS: ATR1, but not ACE1, blockade significantly reduced MMP-1 and -8 concentrations in atheroma supernatants. ACE2 blockade significantly increased MMP-1 and -8 concentrations in atheroma supernatants. AII concentration in atheroma supernatants significantly increased after ATR1, ACE1 and ACE2 blockade. Release of soluble elastin fragments increased after ATR1 and ACE1 blockade, but was not changed by an MMP inhibitor. CONCLUSIONS: Our findings suggest that ATR1 blockade alters AII, MMP-1, MMP-8 expression and a marker of elastin degradation in human atheroma, but that the elastin degradation response is not MMP driven. This data contributes to the recognised ability of ATR1 blockade to modify plaque stability.

Sustained postoperative anaemia is associated with an impaired outcome after coronary artery bypass graft surgery: insights from the IMAGINE trial.

OBJECTIVE: To investigate the association between sustained postoperative anaemia and outcome after coronary artery bypass graft (CABG) surgery. DESIGN: Retrospective analysis of the IMAGINE trial, which tested the effect of the ACE inhibitor quinapril on cardiovascular events after CABG. SETTING: Thoracic surgery clinic/outpatient department. PATIENTS: 2553 stable patients with left ventricular ejection fraction >40% 2-7 days after scheduled CABG. INTERVENTIONS: Randomisation to quinapril or placebo. MAIN OUTCOME MEASURES: Cox regression analysis for the association between postoperative anaemia and cardiovascular events and the effect of quinapril on the incidence of anaemia. RESULTS: Postoperative anaemia was sustained for >50 days in 44% of patients. Sustained postoperative anaemia was associated with an increased incidence of cardiovascular events during the first 3 months (adjusted HR (adjHR) 1.77, 95% CI 1.10 to 2.85, p=0.012) and during the maximum follow-up of 43 months (adjHR 1.37, 95% CI 1.14 to 1.65, p=0.008). When haemoglobin (Hb) was considered as a continuous variable, every 1 mg/dl decrease in Hb was associated with a 13% increase in cardiovascular events (adjHR 0.87, 95% CI 0.81 to 0.95, p=0.003) and a 22% increase in all-cause mortality (adjHR 0.78, 95% CI 0.60 to 0.99, p=0.034). Quinapril was associated with a slower postoperative recovery of Hb levels and a higher incidence of cardiovascular events in patients with anaemia (adjHR 1.60, 95% CI 1.1 to 2.4, p=0.024). CONCLUSIONS: Postoperative anaemia is common, frequently persists for months after CABG surgery and is associated with an impaired outcome. In patients with anaemia, ACE inhibitors slowed recovery from postoperative anaemia and increased the incidence of cardiovascular events after CABG.

Meta-analysis of randomized controlled trials on effect of angiotensin-converting enzyme inhibitors on cancer risk.

The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with ≥1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer.

Ultra-thin-layer chromatography mass spectrometry and thin-layer chromatography mass spectrometry of single peptides of angiotensin-converting enzyme inhibitors.

The separation of structurally related angiotensin-converting enzyme (ACE) inhibitors lisinopril, cilazapril, ramipril and quinapril and their corresponding active diacid forms (prilates) by conventional TLC silica gel 60 plates was contrasted with that afforded by monolithic ultra-thin-layer chromatographic (UTLC) plates. For the use of UTLC plates technical modifications of the commercially available equipments for the sample application, development and detection were made. Plates were developed in modified horizontal developing chamber using ethyl acetate-acetone-acetic acid-water (4:1:0.25:0.5, v/v). Detection of the separated compounds was performed densitometrically in absorption/reflectance mode at 220 nm and after exposure to iodine also by image analysis. The obtained results showed that monolithic layer is more efficient for the separation of structurally similar polar compounds, such as prilates than conventional silica layers. Identification of the compounds was confirmed by ESI-MS after their on-line extraction from the UTLC and TLC plates by means of Camag TLC-MS interface.

Angioedema after nonsteroidal antiinflammatory drug initiation in a patient stable on an angiotensin-converting-enzyme inhibitor.

PURPOSE: A case of angioedema associated with the initiation of a nonsteroidal antiinflammatory drug in a patient stable on an angiotensin-converting-enzyme inhibitor is reported. SUMMARY: A 68-year-old African-American man with no known drug allergies and a history of hypertension, benign prostatic hypertrophy, diverticulosis, and gout arrived at the clinic with swelling of the lips and tongue three days after he started taking naproxen 375 mg every eight hours as needed for pain associated with acute gout. He denied urticaria, difficulty breathing, fever, abdominal pain, vomiting, and diarrhea. His other medications included quinapril 10 mg daily (taken for 5 years), tamsulosin hydrochloride 0.4 mg daily, omeprazole 20 mg daily, and colchicine 0.6 mg daily. He had reported smoking approximately 2.5 packs of cigarettes per week and consuming alcohol (one to two drinks) on the weekends. He denied any illicit drug use, drug rash, or seasonal allergies. Naproxen was discontinued, and the patient was treated with prednisone (tapered regimen) and acetaminophen 650-mg tablets, and his angioedema resolved. The Naranjo et al. probability scale revealed that naproxen and quinapril coadministration was the probable cause of the patient's adverse reaction (score of 7). CONCLUSION: A 68-year-old African-American man who had been receiving quinapril for 5 years developed angioedema after initiation of naproxen.

Renal organic anion transporter-mediated drug-drug interaction between gemcabene and quinapril.

In humans and rats, a synergistic blood pressure reduction was observed when the fibrate gemcabene (CI-1027) was coadministered with the angiotensin-converting enzyme inhibitor quinapril. In a quinapril (3 mg/kg) pharmacokinetic rat study, there was a 40% decrease in urinary excretion and a 53% increase in plasma area under the curve from 0 to 24 h of the active metabolite quinaprilat when coadministered with gemcabene (30 mg/kg). This observation revealed a possible transporter-mediated drug-drug interaction (DDI) between gemcabene and quinapril. This led to a series of studies investigating the underlying clearance mechanisms associated with these compounds intended to elucidate renal transporter interactions between quinapril and gemcabene. In vitro transporter studies using human embryonic kidney 293 cells transfected with human or rat organic anion transporter 3 (hOAT3, rOat3) revealed that quinaprilat is a substrate in both species, with a K(m) value of 13.4 microM for hOAT3. Subsequent studies discovered that gemcabene inhibited quinaprilat uptake by hOAT3 and rOat3 at IC(50) values of 35 and 48 microM, respectively. Moreover, gemcabene acylglucuronide, the major metabolite of gemcabene glucuronidation, also inhibited hOAT3- and rOat3-mediated uptake of quinaprilat at IC(50) values of 197 and 133 microM, respectively. High plasma concentrations of gemcabene (>100 microM) achieved in humans and rats upon oral dosing corroborate with gemcabene inhibition of renal OAT3-mediated secretion of quinaprilat in vitro. This investigation established that a DDI between gemcabene and quinapril involving inhibition of renal transporters and subsequent elevation in plasma concentrations of quinaprilat is responsible for the apparent synergistic blood pressure reduction observed with these compounds.

Angiotensin converting enzyme inhibition enhances collateral artery remodeling in rats with femoral artery occlusion.

Evidence from experimental animal studies indicate that ACE inhibition expands collateral blood flow both in ischemic hearts and peripheral limbs. The present study evaluates whether ACE inhibitor induces collateral blood flow expansion and change of angiogenic gene expression profile in collateral arteries during remodeling. Male Sprague-Dawley rats, weighing 350 g were treated with vehicle (control) or quinapril (ACE inhibitor) at either low dose (3.0 mg/kg) or high dose (18 mg/kg) for 1, 3, 7, 14 days (gene expression) or 16 days (blood flow). All rats received bilateral occlusions of the femoral arteries. Collateral blood flow to the hind limb was assessed by 85Sr and 141Ce-labeled microspheres during treadmill running at 15 and 25 m/min speeds. Quinapril reduced plasma ACE activity by 58% and 88% for the low-dose and high-dose groups, respectively (P < 0.001). High-dose quinapril reduced exercising blood pressure (P < 0.05) and increased hind limb conductance. Collateral blood flows to calf muscles were 51 +/- 3.7, 73 +/- 5.0, and 68 +/- 1.9 mL/min per 100 g in control and quinapril low- and high-dose groups, respectively, during high-speed running (P < 0.001). Real-time RT-PCR revealed that ACE inhibition shifted gene expression to a proangiogenic phenotype in the newly developed collateral arteries. Our findings indicate that ACE inhibition could increase collateral-dependent blood flow and collateral vessel remodeling by promoting proangiogenic gene expression in newly developed collateral arteries. Our results support the potential utility of ACE inhibitor as a therapeutic agent in treating peripheral occlusive arterial disease.

Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.

BACKGROUND: Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. METHODS AND RESULTS: The Ischemia Management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (< or = 7 days) of an angiotensin-converting enzyme inhibitor after CABG reduced cardiovascular events in stable patients with left ventricular ejection fraction > or = 40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio 1.15, 95% confidence interval 0.92 to 1.42, P=0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P=0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG. CONCLUSIONS: In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk.

Influence of enalapril, quinapril and losartan on lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1 beta, IL-6 in spontaneously hypertensive rats (SHR).

Immunopharmacological studies of drugs used in cardiovascular diseases provide new data concerning their modulating effect on the levels of proinflammatory cytokines, chemokines and adhesion molecules. Therefore, we have made an attempt to find out whether enalapril, quinapril and losartan (drugs used in the treatment of arterial hypertension) are able to modulate lipopolysaccharide (LPS)-induced proinflammatory cytokine serum concentrations (tumor necrosis factor alpha - TNF-alpha, interleukin-1 beta _ IL-1 beta, interleukin-6 - IL-6) in spontaneously hypertensive rats (SHR). The animals were divided into four groups as follows: SHR + M (control rats receiving 1% solution of methylcellulose), SHR + E (rats receiving enalapril - 10 mg/kg), SHR + Q (rats receiving quinapril - 10 mg/kg) and SHR + L(rats receiving losartan - 20 mg/kg). 1% solution of methylcellulose and hypotensive drugs were administered by a gavage for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Twenty four hours after the last administration of enalapril, quinapril, losartan or 1% solution of methylcellulose, the rats received a single dose of LPS (ip; 0.1 mg/kg). After 2 h, the rats were anesthetized with ether and the blood samples were collected by heart puncture. Serum TNF-alpha, IL-1 beta and IL-6 concentrations were measured with enzyme-linked immunosorbent assay kits. Additionally, total cholesterol and high density lipoprotein (HDL) cholesterol were evaluated. Enalapril, quinapril and losartan significantly decreased LPS-stimulated TNF-alpha and IL-1 beta level after 21 days. Three-week administration of quinapril lowered IL-6 serum concentration after LPS stimulation. Enalapril and losartan did not affect the IL-6 level. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure. Hypotensive drugs also showed no effect on lipid level. The latest data indicate additional properties of hypotensive drugs. However, further studies are necessary to elucidate precisely the role of proinflammatory cytokines in arterial hypertension.

Influence of preventive therapy with quinapril on IL-6 level in patients with chronic stable angina.

We hypothesized that beneficial role of angiotensin converting enzyme inhibitors in stable coronary artery disease (CAD) therapy may involve (among others) their anti-inflammatory effects, which may be reflected by serum interleukin-6 (IL-6) levels. For that reason, we have investigated the influence of short-term administration of quinapril on serum IL-6 concentration. 124 patients suffering from stable CAD and matched for some of CAD risk factors were enrolled in our study. Patients were randomized to treatment with quinapril or control (placebo administration). Blood samples were taken twice: before and after four weeks of quinapril administration. The effect of quinapril administration was assessed under double-blind placebo-controlled conditions. We observed that quinapril reduced serum IL-6 concentration in almost all studied subgroups of patients (p < 0.001). Interestingly, such an effect was not observed in smokers. Additionally, we found that baseline IL-6 levels were higher in: smokers as compared with nonsmokers (p < 0.001), patients with total cholesterol (TC) to high density lipoprotein (HDL)-cholesterol ratio (TC/HDL-ch ratio) above 5 as compared with subjects with TC/HDL-ch < or = 5 (p = 0.001), and in patients who did not report any statin therapy in comparison with patients undergoing statin treatment (p = 0.023). In conclusion, quinapril may interfere with cytokine release by lowering IL-6 levels, which may be of particular importance for secondary prevention of stable CAD.

Angiotensin-converting enzyme inhibition in patients with coronary artery disease and preserved left ventricular function Ischemia Management with Accupril post-bypass graft via inhibition of angiotensin-converting enzyme (IMAGINE) compared with the other major trials in coronary artery disease.

It has been hypothesized that angiotensin-converting enzyme (ACE) inhibition, independent from its effect on ventricular function and blood pressure, could affect the atherosclerotic process and reduce the incidence of ischemic events and its complications. Several large clinical outcome trials were designed to test this hypothesis: QUIET, HOPE, EUROPA, PEACE, and IMAGINE. The results of the PEACE study were recently reported, leaving the IMAGINE study as the last chapter in our efforts to evaluate the role of ACE inhibition in coronary artery disease with preserved left ventricular function. In this report, we compare these studies with respect to their methodology and patient population and analyze the unique nature of the last ongoing study, IMAGINE. The reported studies show that patients with coronary artery disease who are at low-to-moderate or high risk should receive an ACE inhibitor if tolerated. However, when the absolute risk of a patient decreases, and intensive contemporary management is given, with good control of risk factors, the absolute and perhaps relative benefits of an ACE inhibitor decrease and their routine use in these patients may not be warranted. The role of ACE inhibition started early post-coronary artery bypass graft in patients with preserved left ventricular function, and intensive contemporary management remains to be determined and should get answered by the IMAGINE study. Moreover, the IMAGINE population is not only a lower risk population than those enrolled in HOPE or EUROPA, but also the risk for this population is bimodal in nature (early post-revascularization inflammation and thrombosis vs long-term atherosclerosis progression) and may provide further insight into underlying mechanisms.

Correlation of flow mediated dilation with inflammatory markers in patients with impaired cardiac function. Beneficial effects of inhibition of ACE.

Impaired cardiac function is frequently accompanied by peripheral vascular dysfunction and a pro-inflammatory condition, which may be associated with elevated levels of angiotensin II. We hypothesized that the magnitude of flow mediated dilatation (FMD) of the brachial artery of post myocardial infarction patients will correlate with serum levels of tumor necrosis factor alpha (TNFalpha) and C-reactive protein (CRP), and that treatment with angiotensin converting enzyme inhibitors (ACEI) will increase FMD by reducing TNFalpha and CRP. Patients were treated with low dose (10 mg/day) quinapril (Q) or enalapril (E) and their effects on FMD and inflammatory markers were evaluated after 8 and 12 weeks. Before treatment, in both groups FMD showed a low value (Q: 2.95+0.42% and E: 3.3+/-0.33%), whereas TNF-alpha (Q: 31.65+/-8.23 pg/ml and E: 29.5+/-5.9 pg/ml) and CRP (Q: 7.28+/-2.96 mg/ml and E: 7.08+/-3.02 mg/ml) were elevated. In the Q group, but not in the E group FMD increased significantly, (to 5.96+1.10%), whereas TNF-alpha (19.0+/-12.21 pg/ml) and CRP (to 3.91+/-1.82 mg/L) significantly decreased after 8 and 12 weeks of Q treatment. Moreover, the magnitude of FMD showed a strong inverse correlation with serum levels of TNF-alpha and CRP after Q treatment. Thus, in post myocardial infarction patients endothelial dysfunction assessed by FMD correlates with elevated levels of plasma inflammatory markers, and low dose quinapril improves endothelial function, likely by reducing vascular inflammation.

Effects of Angiotensin-converting enzyme inhibition and statin treatment on inflammatory markers and endothelial functions in patients with longterm rheumatoid arthritis.

OBJECTIVE: To investigate the effects of angiotensin-converting enzyme (ACE) inhibitors and statins (hydroxy-methyl-glutaryl-CoA reductase inhibitors) on inflammatory markers and endothelial functions in patients with rheumatoid arthritis (RA). METHODS: A total of 45 patients with longterm RA were randomized into 3 groups to receive 8 weeks of treatment with placebo (n = 15), simvastatin (20 mg/day, n = 15), or quinapril (10 mg/day, n = 15) as an adjunct to existing antirheumatic drug treatment. Factors with a role in the development of endothelial dysfunction, such as C-reactive protein (CRP), fibrinogen, nitric oxide (NO), and serum cytokine concentrations including interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured at baseline and in the posttreatment period. Brachial artery vasodilator responses were assessed by high resolution ultrasound to evaluate endothelial functions. RESULTS: Simvastatin treatment significantly decreased serum CRP and TNF-a [from 14 +/- 6 to 7 +/- 3 mg/l (p = 0.025) and 30 +/- 5 to 16 +/- 4 pg/ml (p = 0.012), respectively], while quinapril had no significant changes in these 2 measures. IL-1beta and IL-6 showed insignificant changes in patients in the 2 drug groups. Endothelium-dependent vasodilatation was improved significantly in the simvastatin group [from 5.3 +/- 1.1% to 8.9 +/- 1.4% (p = 0.025)], while there was no difference in endothelium-independent vasodilatation [9.0 +/- 1.8% to 11.2 +/- 2.5% (p = 0.17)]. The quinapril group showed no significant changes in both types of vasodilation although there was a tendency to an increase in endothelium-dependent vasodilatation [from 6.1 +/- 0.8% to 7.8 +/- 0.7% (p = 0.06)]. Treatment with the 2 drugs had no significant effects on resting arterial diameter. CONCLUSION: We show that simvastatin 20 mg daily improves endothelial function in patients with RA. Its beneficial effect may be attributed to lowering CRP and TNF-alpha concentrations. ACE inhibition with daily 10 mg quinapril was found to have no significant effects on inflammatory markers and endothelial vasodilator response.