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Angiotensin II, which is also thought to play a key role in atherosclerosis, has recently been shown to have pro-oxidant effects, by increasing superoxide (•O2 −) production in human arteries.1 Oxidative stress, a state of excessive free radical activity which is associated with reduced bioavailable nitric oxide (NO), may be evident in patients with coronary heart disease (CHD).2 Lately ACE inhibitors have been shown to reduce cardiovascular morbidity and mortality in patients at high risk of CHD.3 The aim of the present study was to determine, which, if any, risk factors and drug treatments were associated with altered free radical concentrations in the arteries of CHD patients undergoing coronary artery bypass grafting (CABG).
Seventy nine consecutive patients who were undergoing CABG were prospectively included in this study. Patient characteristics were determined by review of case records. A history of current cigarette smoking, hypertension (defined as either current antihypertensive treatment or a blood pressure > 140/90 mm Hg), diabetes mellitus, and hypercholesterolaemia (plasma cholesterol > 5.5 mmol/l) were considered as risk factors for CHD.
Distal segments of left internal mammary artery which were obtained at the time of CABG were taken to the laboratory in Krebs-Hepes buffer (pH 7.4 ± 0.2), carefully dissected free of loose connective tissue, divided into 4–5 mm segments and weighed. Vascular •O2 − was measured by lucigenin enhanced chemiluminescence in a liquid scintillation counter (Hewlet Packard Model Tricarb 2100TR).1 Absolute counts were quantified with a xanthine/xanthine oxidase calibration curve for •O2 − generation and reported as picomol per milligram per minute of tissue. Statistical analyses of vascular •O2 − concentrations after log transformation were undertaken using the non-parametric Mann-Whitney Test and a stepwise multiple regression analysis was also performed. A probability value of p < 0.05 was considered significant. This study was approved by the hospital's ethics committee.
Data on age, sex, risk factors, and drug treatment are given in table1. The profiles of risk factors and different classes of drug treatments were similar between patients who were taking an angiotensin converting enzyme (ACE) inhibitor or an angiotensin type 1 receptor antagonist (ARA), compared to those who were not taking these treatments.
An ACE inhibitor or ARA was prescribed in 16 and three patients, respectively. The median rate of production of •O2 − in internal mammary arteries was 1137 (interquartile range (IQR) 1290) pmol/mg/min. Superoxide concentrations were lower in those patients taking either an ACE inhibitor or an ARA (857 (IQR 670) pmol/mg/min; n = 19) compared to those who were not (1600 (IQR 1511) pmol/mg/min; n = 60; p = 0.002; 95% confidence interval for median difference 487 to 1228 pmol/mg/min (fig 1)). No other associations between age, sex, risk factors or drug treatments and superoxide concentrations were identified.
We have shown, for the first time in human arteries, that •O2 − concentrations were lower in patients treated with either an ACE inhibitor or an ARA, compared to those who were not. The clinical characteristics of both of these groups were similar such that the observed differences in vascular •O2 − concentrations were unlikely to be explained by any other patient characteristic or treatment. It is of interest that despite the fact that a large proportion of these patients were taking drugs with putative antioxidant properties, such as aspirin, β blockers and HMG-CoA reductase inhibitors, vascular free radical concentrations were detected at physiologically important concentrations. The absence of any important antioxidant effect of these other treatments suggests that the sample size may not be sufficiently large to detect what may be a lesser antioxidant effect of these drugs. The variation in basal vascular •O2 − concentrations observed in this and other investigations in humans,4 ,5 and the lack of correlation of •O2 − production with some atherosclerotic risk factors, may be caused by the heterogeneous clinical characteristics of patients with CAD.
Our observations raise two questions. The first is how does such treatment exert this effect? Though some ACE inhibitors may have direct free radical scavenging properties, this effect has been difficult to show at therapeutic concentrations in humans.6 A more likely explanation is that the antioxidant effect of this treatment is caused by inhibition of the effects of angiotensin II.1The second question is what, if any, might be the therapeutic significance of this effect of RAS inhibitors? A reduction in vascular free radical production associated with RAS inhibition, as is the case in the current study, may lead to enhanced bioavailable nitric oxide in vivo.
Taken together, these observations suggest that RAS inhibition leads to a reduction in oxidative stress in patients with CHD. Given the damaging effects of increased free radical activity in the vasculature, the antioxidative effects of these treatment may be one further mechanism which may contribute to their beneficial effects in patients with CHD.
Sources of support: CB is a Medical Research Council Clinical Training Fellow. This work is also supported by a British Heart Foundation Programme Grant (RG97009) to AFD.