Quinapril, an ACE Inhibitor, Reduces Markers of Oxidative Stress in the Metabolic Syndrome

Metabolic Syndrome/Insulin Resistance Syndrome/Pre-Diabetes ORIGINAL ARTICLE Quinapril, an ACE Inhibitor, Reduces Markers of Oxidative Stress in the Metabolic Syndrome 1 3 BOBBY V. KHAN, MD, PHD W. CRAIG HOOPER, PHD ing the link between inflammation, met- 1 1 SRIKANTH SOLA, MD REKHA G. MENON, MD abolic disorders, and cardiovascular 1 1 WRIGHT B. LAUTEN, BS STAMATIOS LERAKIS, MD 2 1 disease (5,6). Chronic inflammation and RAMA NATARAJAN, PHD TAREK HELMY, MD an abnormal pro-oxidant state are both found in the metabolic syndrome and may play a role in its pathogenesis (7,8). The renin-angiotensin system (RAS) plays a central role in the pathogenesis of OBJECTIVE — Patients with the metabolic syndrome often have abnormal levels of proin- atherosclerosis-related diseases. Angio- flammatory and pro-oxidative mechanisms within their vasculature. We sought to determine tensin II, the central molecule in the RAS, whether the ACE inhibitor quinapril regulates markers of oxidative stress in the metabolic syndrome. has multiple effects on inflammation, oxidation, atherosclerotic plaque initiation, RESEARCH DESIGN AND METHODS — Forty patients with the metabolic syndrome and progression (9). In the present study, were randomized in a double-blind manner to either the ACE inhibitor quinapril (20 mg/day) or we determine potential mechanisms by matching placebo for 4 weeks. Serum markers of vascular oxidative stress were measured. which the administration of the ACE inhibitor quinapril regulates mechanisms of RESULTS — After 4 weeks of therapy, serum 8-isoprostane was reduced by 12% in the oxidative stress in subjects with the met- Ϯ Ϯ quinapril group when compared with placebo (quinapril, 46.7 1.0; placebo, 52.7 0.9 abolic syndrome. pg/ml; P ϭ 0.001). Erythrocyte superoxide dismutase activity increased 35% in the quinapril Ϯ Ϯ group when compared with placebo (quinapril, 826.3 17.1; placebo, 612.3 6.9 units/g Hb; RESEARCH DESIGN AND P Ͻ 0.001). In addition, lag time to oxidation of LDL, a marker of oxidative stress, was increased Ϯ METHODS — Men and women aged by 48% in the quinapril group when compared with placebo (quinapril 89.2 9.2 vs. placebo Ն 60.1 Ϯ 12.3 min; P Ͻ 0.001). Therapy with quinapril was well tolerated. 18 years and with the metabolic syndrome were enrolled in the study. The CONCLUSIONS — The addition of the ACE inhibitor quinapril reduces markers of vascular metabolic syndrome was defined using oxidative stress and may attenuate the progression of the pathophysiology seen in the metabolic the National Cholesterol Education Pro- syndrome. gram Adult Treatment Panel III criteria (Table 1), and eligible subjects were re- Diabetes Care 27:1712–1715, 2004 quired to meet at least three of the five criteria (10). Subjects were excluded if they had any of the following: tobacco use he metabolic syndrome is a constel- pared with those without metabolic syn- Ͻ6 months before enrollment, a clinical lation of abnormal glucose and lipid drome (2). history of coronary artery disease or con- T metabolism that has reached epi- Recent studies (3,4) suggest that pro- gestive heart failure, use of an ACE inhib- demic proportions over the last decade oxidative and proinflammatory processes itor or angiotensin receptor blocker Ͻ12 (1). Patients with the metabolic syndrome play a significant role in the progression of months before enrollment, ejection frac- are at considerable risk for developing atherosclerosis. In fact, inflammatory tion Ͻ50% by echocardiography or con- atherosclerosis-related diseases, includ- markers are predictors of cardiovascular trast ventriculogram, systolic blood Ͼ Ͻ ing a two- to fourfold increased risk of events and progression to type 2 diabetes pressure 140 or 100 mmHg, diastolic blood pressure Ͼ90 or Ͻ60 mmHg, stroke and a three- to fourfold increased in healthy individuals as well as those Ͼ Ͼ risk of myocardial infarction when com- with the metabolic syndrome, underscor- HbA1c 7.0%, serum creatinine 2.0 mg/dl, hepatic impairment, or malig- nancy. Written informed consent was ob- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tained from all subjects. From the 1Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; the 2Division of 3 Diabetes and Endocrinology, City of Hope Medical Center, Duarte, California; and the Centers for Disease Study design Control and Prevention, Atlanta, Georgia. Address correspondence and reprint requests to Bobby V. Khan, MD, PhD, Division of Cardiology, Subjects were randomized in a double- Department of Medicine, Emory University School of Medicine, 69 Jesse Hill Dr. SE, #C247, Atlanta, GA blinded fashion to either quinapril 20 mg/ 30303. E-mail: [email protected]. day or matching placebo for 4 weeks. Received for publication 10 February 2004 and accepted in revised form 1 April 2004. Allocation concealment was maintained Abbreviations: E-SOD, erythrocyte superoxide dismutase; RAS, renin-angiotensin system; A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion until the end of the study. The dose of the factors for many substances. study drug was chosen based on the re- © 2004 by the American Diabetes Association. sults of prior studies in which we found 1712 DIABETES CARE, VOLUME 27, NUMBER 7, JULY 2004 Khan and Associates Table 1—Diagnostic criteria for the metabolic syndrome Statistical analysis All data are presented as the mean Ϯ SE. Factor Criteria Comparisons were determined within the ACE inhibitor and placebo groups using 1 Abdominal girth Ͼ40 in (102 cm) in men or Ͼ35 in (88 cm) in women paired-sample t tests. A P value of Ͻ0.05 2 HDL cholesterol Ͻ40 mg/dl in men or Ͻ50 mg/dl in women was considered statistically significant, 3 Fasting triglycerides Ͼ150 mg/dl (1.69 mmol/l) and all P values were two sided. Calcula- 4 Blood pressure Ͼ130/85 mmHg tions were performed with SPSS software 5 Fasting glucose Ն110 mg/dl (Ն 6.1 mmol/l) (version 10.0; Statistical Package for the Three out of five criteria are required for diagnosis of the metabolic syndrome. Social Sciences, Chicago, IL). that the addition of quinapril 20 mg daily LDL oxidation and lag time to standard therapy in subjects with cor- We have previously observed that the ad- RESULTS — Forty subjects (23 men onary artery disease reduced markers of ministration of an RAS inhibitor to sub- and 17 women) were enrolled in the inflammation and oxidative stress; these jects with coronary artery disease study and followed for 4 weeks. Fol- changes were independent of blood pres- increases the lag time to oxidation of LDL low-up was 100% complete. The two ex- sure reduction (11). Subjects were ad- cholesterol, suggesting increased resis- perimental groups (quinapril and placebo) had similar demographic char- vised to self-administer one-half of the tance to the modification of LDL choles- acteristics (Table 2). The mean age was full dose during the initial 2 days of ther- terol (15). LDL cholesterol was isolated 2 apy, after which they were to take the full 36.2 years; mean BMI 29.3 kg/m ; mean from blood samples. Using CuSO4, oxi- study dose. After 2 weeks, blood pressure LDL cholesterol, HDL cholesterol, and dation of LDL was performed. Spectro- Ϯ was rechecked and blood was drawn to triglyceride levels were 125.9 20.3 photometric analysis was used to Ϯ Ϯ measure serum creatinine and potassium. mg/dl (3.3 0.5 mmol/l), 39.7 5.9 determine the lag time to oxidation of (1.04 Ϯ 0.13), and 229 Ϯ 33 (6 Ϯ 0.8), Fasting blood samples were drawn before LDL (16). We found no evidence of inter- and at the end of therapy at a similar time respectively; mean systolic and diastolic ference of quinapril or its metabolite in Ϯ of day. The study protocol complies with blood pressures were 125.9 8.2 and the LDL oxidation assays. Ϯ the Declaration of Helsinki and was ap- 79.5 10.6 mmHg, respectively; and the Blood glucose was measured using a proved by the institutional review board mean fasting glucose was 112 mg/dl. Nine glucose dehydrogenase method after pre- at the participating institution before its subjects (23%) were on lipid-lowering implementation. cipitation of proteins by trichloroacetic therapy. No statistically significant differ- acid. LDL and HDL fractions were sepa- ences were noted in baseline characteris- Measurement of total serum rated from fresh serum by combined ul- tics between the two treatment groups. 8-isoprostane and erythrocyte tracentrifugation and precipitation. There was a higher incidence of superoxide dismutase Lipoprotein fraction cholesterol and trig- cough in the quinapril group when com- ϭ Plasma samples were centrifuged and lycerides were measured enzymatically. pared with the placebo group (4 vs. 1; P stored at Ϫ80°C. An aliquot was drawn, and enzyme immunoassay (EIA; Cayman Chemical, Ann Arbor, MI) for serum 8-iso- Table 2—Patient demographics and baseline characteristics prostane was performed on each sample in ␮ triplicate. Serum (60 l) was used for anal- Quinapril Placebo ysis, and enzyme immunoassay was performed as previously described (12). The n 20 20 levels of total serum 8-isoprostane were de- Age (years) 35.2 39.6 termined on a plate reader at an optical den- Sex (M/F) 11/9 12/8 sity of 420 nm. Erythrocyte superoxide BMI (kg/m2) 29.8 29.1 dismutase (E-SOD) activity was determined Systolic blood pressure (mmHg) 126 Ϯ 8 130 Ϯ 9 using hemolysates and commercially avail- Diastolic blood pressure (mmHg) 80 Ϯ 10.4 77.8 Ϯ 11.1 able kits (cat. no. SDI 25; Randox Labora- LDL cholesterol (mg/dl) 124.7 Ϯ 21.4 130 Ϯ 16.8 tories, Crumlin, Ireland). Briefly, HDL cholesterol (mg/dl) 40.3 Ϯ 7.0 38.9 Ϯ 6.1 superoxide radicals produced by xanthine Triglycerides (mg/dl) 238 Ϯ 36 219 Ϯ 30 and xanthine oxidase reacts with 2-(4- Fasting glucose (mg/dl) 113 Ϯ 15 111 Ϯ 19 Ϯ Ϯ iodophenyl)-3-(4-nitrophenol)-5- HbA1c (%) 5.8 0.7 5.6 0.8 phenyltetrazolium chloride to form a red Hypertension 5 (25) 6 (30) formazan dye (13).

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