Syed T. Rahman

Irbesartan, an angiotensin type 1 receptor inhibitor, regulates the vascular oxidative state in patients with coronary artery disease ☆

OBJECTIVES The aim of this study was to determine the effect of angiotensin II type 1 (AT(1)) receptor antagonists on pro-oxidant species observed in the pathogenesis of atherosclerosis. Parameters such as low-density lipoprotein (LDL) susceptibility, monocyte binding capacity, superoxide generation and lipid peroxidation were examined in the presence of the AT(1) receptor antagonist irbesartan. BACKGROUND Low-density lipoprotein oxidation is a key component in the process of atherogenesis. This modification may involve various mechanisms, including changes in nitric oxide levels and superoxide levels. Additionally, compounds that suppress these mechanisms may retard or inhibit the pathogenesis of atherosclerosis. METHODS Forty-seven patients with documented coronary artery disease were treated with irbesartan for a 12-week period. Patients were randomized to receive irbesartan or placebo. Lipid peroxidation, superoxide levels, monocyte binding and LDL oxidation were measured at 0, 4 and 12 weeks. Findings were statistically evaluated by two-way repeated measures analysis of variance with p < 0.05 being significant. RESULTS Treatment with irbesartan significantly decreased the pro-oxidative environment seen in our study population. Lag time for LDL oxidation increased 32% at 12 weeks, suggesting an increased resistance of LDL modification in the serum. Thiobarbituric acid reactive substances activity indicated that lipid peroxidation decreased by 36% in comparison to placebo. In addition, superoxide levels and monocyte-binding capacity were also significantly reduced in coronary artery disease patients receiving irbesartan. CONCLUSIONS Our results indicate that irbesartan may suppress the atherosclerotic process by inhibiting the intravascular oxidative state and the production of reactive oxygen species, compounds that may cause damage to the vasculature.

Effects of Eprosartan Versus Hydrochlorothiazide on Markers of Vascular Oxidation and Inflammation and Blood Pressure (Renin-Angiotensin System Antagonists, Oxidation, and Inflammation)

Antagonists of the renin-angiotensin system, such as angiotensin type 1 (AT(1)) receptor inhibitors and angiotensin-converting enzyme inhibitors, are becoming increasingly popular agents in treating patients with systemic hypertension and minimizing organ damage. In the present study, we compared the effects of eprosartan, an AT(1) receptor inhibitor, with the diuretic hydrochlorothiazide in a group of newly diagnosed hypertensive patients with multiple risk factors for atherosclerosis. The subjects were monitored and tested at 0 and 4 weeks to determine their individual effects on vascular and inflammatory markers. Although blood pressure reduction was comparable between the 2 agents, there were notable differences in their effects on markers of inflammation and oxidation. We observed a 28% reduction in neutrophil superoxide anion generating capacity, a 34% reduction in soluble monocyte chemotactic protein-1, and a 35% reduction in soluble vascular cell adhesion molecule with eprosartan therapy (all p <0.05 from the start of therapy). In addition, eprosartan showed further benefit in its ability to increase low-density lipoprotein oxidation lag time, suggesting an increased resistance to oxidation and/or modification of low-density lipoprotein. Although hydrochlorothiazide was effective in blood pressure reduction, there were no significant changes in any of the above parameters after 4 weeks of treatment. These findings suggest that eprosartan, an AT(1) receptor inhibitor, effectively reduces systemic blood pressure and, compared with hydrochlorothiazide, suggests additional benefits in the vasculature by inhibiting mechanisms of inflammation and oxidation.

Usefulness of quinapril and irbesartan to improve the anti-inflammatory response of atorvastatin and aspirin in patients with coronary heart disease

A that inhibit the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers, have considerable benefit in hypertension and heart failure.1–3 These compounds decrease hemodynamic stress, increase nitric oxide bioactivity, and reduce pulse pressure.4–6 Recent longterm clinical studies have indicated that the addition of an ACE inhibitor decreases morbidity and mortality in patients with stable coronary artery disease.7,8 Furthermore, we have previously demonstrated that treatment with irbesartan in patients with early atherosclerosis decreases markers of inflammation that may be sensitive to the oxidative state in the vasculature.9,10 In the present study, we examine the potential mechanisms by which the addition of either quinapril or irbesartan can regulate vascular function in patients already on a regimen of aspirin and atorvastatin therapy. • • • One hundred twelve subjects (64 men and 48 women) with coronary artery disease and with a systolic blood pressure of 140 mm Hg were enrolled into the study from several medical facilities in metropolitan Atlanta, Georgia. All patients had been on antianginal therapy, had undergone coronary artery bypass graft surgery, and/or had undergone percutaneous transluminal coronary angioplasty 6 months before the start of the study. All patients were considered stable on their medical regimen and free of any acute coronary syndrome or subjective symptoms of chest pain for 6 months. Patients were started on atorvastatin (10 to 40 mg/day) to obtain a target lowdensity lipoprotein cholesterol of 100 mg/dl. Serum was collected and stored at the initiation of atorvastatin therapy. All subjects were on aspirin (81 to 325 mg/day), and an equal number of subjects in each group were on nitrates and blockers. No patient had taken ACE inhibitors or AT1 receptor inhibitors for 6 months before the beginning of the study. A survey was performed of each potential subject, and the following were excluded: those with a medical necessity for ACE inhibitor therapy, current smokers, and subjects with acute or previous myocardial infarction, an ejection fraction 35% by echocardiography or ventriculography, diabetes with a glycosylated hemoglobin 8.5%, systolic blood pressure 140 mm Hg, serum creatinine 2.2 mg/dl, or active malignancy. The study protocol was approved by the research committee at Emory University, and all subjects provided written, informed consent. The subjects were placed on atorvastatin for an average of 3.7 months (range 1.9 to 5.3) to reach a target low-density lipoprotein cholesterol of 100 mg/dl. Using a randomized, open-label, crossover protocol, subjects received quinapril 20 mg/day (Pfizer Inc., New York, New York) (n 39), irbesartan 150 mg/day (Bristol-Myers Squibb and Sanofi-Synthelabo, Princeton, New Jersey) (n 37), or placebo (n 36) for 24 weeks. Serum samples were collected at 5 time intervals: (1) the start of atorvastatin; (2) start of quinapril, irbesartan, or placebo; (3) 4 weeks of quinapril, irbesartan, or placebo; (4) 12 weeks of quinapril, irbesartan, or placebo; and (5) 24 weeks of quinapril, irbesartan, or placebo. Whole blood immunotyping was performed in blood samples by fluorescence-activated cell sorting analysis using a monoclonal antibody to the human CD11b receptor, a protein with human binding sites and a very high binding affinity to human monocytes. The monoclonal antibody to the CD11b receptor was obtained through Pharmingen/BD Biosciences (Lexington, Kentucky). Using flow cytometry analysis, the changes in monocyte CD11b expression were determined as previously described.5,10 The plasma samples were centrifuged and stored at 20°C. Enzyme-linked immunosorbent assays (ELISA) for soluble interleukin-6 (sIL-6) were performed on each sample in triplicate (ELISA kits, Biosource International, Camarillo, California). Two hundred microliters of serum was used for analyses, and ELISA was performed as previously described.9 The levels of sIL-6 were read using an ELISA plate reader at an optical density of 450 nm. All data are presented as the mean value SEM. Comparisons were determined within the quinapril and irbesartan groups and between the quinapril and irbesartan groups with 2-way analysis of variance. A p value of 0.05 was considered statistically significant. (Bonferroni correction was applied; p values were related to analysis of variance.) From the Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; and University of Michigan, Division of Cardiology, Ann Arbor, Michigan. Dr. B. Khan was supported by the Emory Medical Care Foundation, Atlanta, Georgia, and Dr. Parthasarathy was supported by grant R01-HL34453 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. B. Khan’s address is: Emory University School of Medicine, Division of Cardiology, 69 Jesse Hill Drive SE, C233, Atlanta, Georgia 30303. E-mail: bkhan@emory.edu. Manuscript received July 8, 2002; revised manuscript received and accepted January 20, 2003.

The impact of lipoic acid on endothelial function and proteinuria in quinapril-treated diabetic patients with stage I hypertension: results from the QUALITY study.

Background: We sought to determine whether a combination of angiotensin-converting enzyme inhibitors (ACEIs) and the nutraceutical α-lipoic acid (ALA) regulates blood pressure, endothelial function, and proteinuria in diabetic patients with Stage I hypertension. Methods: A total of 40 diabetic patients with Stage I hypertension were treated in a crossover double-blinded manner. Patients were administered quinapril ([QUI] 40 mg/d) for 8 weeks or QUI + ALA (600 mg/d) for 8 weeks. Measurements included blood pressure, 24-hour collection of urinary albumin, and endothelial-dependent flow-mediated dilation (FMD). Results: There was a change of metabolic parameters in both study groups after 8 weeks of therapy. In comparison to baseline, the 24-hour urinary albumin significantly decreased by 30% in the QUI group (P = .018, time comparison) and 53% in QUI + ALA group (P < .005, time and group comparison). Also, when compared with baseline, FMD significantly increased by 58% in QUI group (P < .005, time comparison) and by 116% in QUI + ALA group (P < .005, time and group comparison). Systolic and diastolic blood pressure reduced significantly by 10% with QUI treatment. There was no further blood pressure reduction when patients were administered both QUI and ALA. Conclusions: In diabetic patients with hypertension, QUI reduces blood pressure, proteinuria, and improves endothelial function. Moreover, this effect is strongly potentiated with a combination of QUI and ALA. These results may attenuate the progression of vascular pathophysiology seen in patients with a combination of diabetes and hypertension.

Nebivolol in High-Risk, Obese African Americans With Stage 1 Hypertension: Effects on Blood Pressure, Vascular Compliance, and Endothelial Function

The authors sought to determine whether nebivolol treatment results in changes in blood pressure (BP), nitric oxide bioavailability, and vascular function in obese African Americans with recently diagnosed stage 1 hypertension. Forty‐three obese, hypertensive African Americans (mean BP: systolic, 148.8±14.3 mm Hg; diastolic, 90.4±8.2 mm Hg) were treated with nebivolol (5–10 mg/d) for 8 weeks. Primary outcomes were change in systolic and diastolic BP and efficacy in reaching normotensive BP. Mean systolic BP decreased by 9.2±14 mm Hg (P<.005) and diastolic BP decreased 6.8±9 mm Hg (P<.005) with 8 weeks of therapy. Significant improvements were seen in arterial compliance with nebivolol treatment as measured by aortic augmentation index (P<.005) and time to wave reflection (P=.013). Nebivolol treatment improved endothelial function as measured by flow‐mediated dilation (P<.005). Levels of erythrocyte cellular superoxide dismutase increased with nebivolol, indirectly suggesting increased bioavailability of nitric oxide (P<.005). Monotherapy with nebivolol in obese, hypertensive African Americans results in significant systolic and diastolic BP reduction by mechanisms that include improved vascular function and compliance.

Vascular Effects of Nebivolol Added to Hydrochlorothiazide in African Americans With Hypertension and Echocardiographic Evidence of Diastolic Dysfunction The NASAA Study

Background: African Americans have greater risk of cardiovascular events than comparator populations of white European origin. A potential reason for this is reduced nitric oxide bioavailability in African Americans, resulting in increased prevalence of factors that contribute to ventricular dysfunction. We investigated the effects of nebivolol with the diuretic hydrochlorothiazide (HCTZ) in hypertensive African Americans with echocardiographic evidence of diastolic dysfunction. Methods: A total of 42 African American patients were assigned to nebivolol and HCTZ in an open-label fashion for a 24-week period. Changes in blood pressure (BP), echocardiographic parameters, and success in attaining target BP were determined. As an indirect determinant of endothelial function, serum total nitric oxide (NOx) levels and asymmetric dimethyl arginine (ADMA) levels were performed at baseline and after the treatment period. Results: The systolic BP decreased from 150 ± 13 to 136 ± 16 mm Hg (P < .005). Diastolic BP decreased from 94 ± 13 to 84 ± 9 mm Hg (P = .008). Of the patients that completed the study, 77% achieved a combined target BP of systolic BP <140 mm Hg and a diastolic BP <90 mm Hg. Serum NOx increased by 41% and 39% in patients that were treated with 10 mg and 20 mg daily nebivolol, respectively. The ADMA levels decreased by 44% following treatment. The change in systolic BP was strongly correlated to the change in ADMA (r = .54; P = .024). Furthermore, in comparison to a group of age-matched patients controlled with diuretic therapy only, the ADMA levels were significantly lower in the nebivolol posttreatment group (controlled BP with diuretic: 0.32 ± 0.07μmol/L; nebivolol posttreatment: 0.24 ± 0.06 μmol/L; P < .05). Conclusion: Reduced BP with nebivolol in hypertensive African Americans and echocardiographic evidence of diastolic dysfunction correlates with improved endothelial function. Furthermore, improvement in endothelial function and increased nitric oxide bioavailability suggests a potential mechanism of efficacy of nebivolol in these patients.

Changes in Central Aortic Pressure, Endothelial Function and Biomarkers in Hypertensive African-Americans with the Cardiometabolic Syndrome: Comparison of Amlodipine/Olmesartan versus Hydrochlorothiazide/Losartan

Sixty-six self-identified African-American subjects with stage 1 and 2 hypertension and characteristics of the cardiometabolic syndrome were treated with amlodipine/olmesartan (A/O) versus losartan/hydrochlorothiazide (L/H) for 20 weeks in an open-label, active comparator fashion. Subjects not meeting a blood pressure (BP) value of <125/75 mm Hg on either regimen at week 14 were placed on additional or alternative therapy. After 20 weeks of therapy, systolic BP was reduced by 34.6 ± 4.2 mm Hg in the A/O group and by 27.0 ± 4.1 mm Hg in the L/H group (p = 0.012 A/O vs. L/H). Diastolic BP was reduced by 16.9 ± 2.0 mm Hg in the A/O group and by 12.3 ± 2.0 mm Hg in the L/H group (p = 0.022 A/O vs. L/H). There was a substantial increase in endothelial function of 44 and 103% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H). Central aorta augmentation pressure was significantly reduced by 42% with the A/O treatment, and a smaller, significant reduction of 28% was observed with the L/H treatment (p = 0.034 A/O vs. L/H). There was a reduction in sIL-6 levels of 20 and 33%, a reduction in serum leptin levels of 22 and 40%, and an increase in serum adiponectin of 19 and 46% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H for each biomarker). Treatment with A/O after 14 weeks reduced pulse wave velocity by 22% (p = 0.011 time comparison), whereas L/H treatment had no significant effect. Our findings suggest that, in addition to effective BP reduction, A/O differentially regulates markers of inflammation and obesity, thereby potentially providing greater vascular protection.

Contents Vol. 3, 2013

S. Brietzke, Columbia, Mo. M. Bursztyn, Jerusalem K.C. Dellsperger, Augusta, Ga. V. DeMarco, Columbia, Mo. J.P. Dwyer, Nashville, Tenn. K.C. Ferdinand, New Orleans, La. J.M. Flack, Detroit, Mich. E.P. Gomez-Sanchez, Jackson, Miss. M.R. Hayden, Camdenton, Mo. E.J. Henriksen, Tucson, Ariz. J.M. Luther, Nashville, Tenn. F. Murad, Washington, D.C. C. Ronco, Vicenza N. Stern, Tel Aviv C.S. Stump, Tucson, Ariz. A.T. Whaley-Connell, Columbia, Mo. Founded 2011 by J.R. Sowers CardioRenal Medicine

EFFECTS OF NEBIVOLOL ON LEVELS OF MARKERS OF INFLAMMATION AND OBESITY IN RESPONSE TO EXERCISE-INDUCED STRESS: STUDIES IN OBESE AFRICAN-AMERICAN PATIENTS WITH STAGE I HYPERTENSION

Background: There is a disproportionate burden of hypertension in African-Americans and less than 30% of African-Americans achieve blood pressure control with medications. Regulation of adipose tissue may represent an important link between increased insulin resistance, hypertension, and obesity, all key factors in the metabolic syndrome. Inflammation is involved in multiple stages of the development of atherosclerosis and serum levels of inflammatory markers including sVCAM-1 and sIL-6 may be used to predict cardiovascular disease risk. Nebivolol is a highly cardioselective vasodilatory beta1 receptor blocker that lowers blood pressure. We sought to determine whether nebivolol has beneficial effects on vascular markers of inflammation and oxidation in obese African-American patients with hypertension when exposed to exercise-induced stress.