Decreased Serum Angiotensin-converting Enzyme Research Articles

The effect of angiotensin-converting enzyme levels on COVID-19 susceptibility and severity: a Mendelian randomization study.

BackgroundThere has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the COVID-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or COVID-19 severity, while reducing potential bias from confounding and reverse causation in observational studies.MethodsGenetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for COVID-19 susceptibility, hospitalization and severe-disease outcome.ResultsGenetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in COVID-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results.ConclusionGenetically decreased serum ACE levels were not associated with susceptibility to, or severity of, COVID-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the COVID-19 pandemic.

Hesperidin inhibits L-NAME-induced vascular and renal alterations in rats by suppressing the renin-angiotensin system, transforming growth factor-β1, and oxidative stress.

The protective effect of hesperidin on vascular and renal alterations and possible underlying mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats were investigated in this study. Male Sprague-Dawley rats were administered L-NAME (40mg/kg/day), L-NAME plus hesperidin (30mg/kg/day), and L-NAME plus captopril (2.5mg/kg/day) for 5weeks. Hesperidin and captopril significantly prevented L-NAME-induced hypertension, vascular and renal dysfunction, intrarenal artery remodelling, glomerular extracellular matrix accumulation, and renal fibrosis. The preventive treatment with hesperidin and captopril also significantly decreased serum angiotensin-converting enzyme activity and plasma transforming growth factor-β1 (TGF-β1) levels and downregulated angiotensin II receptor type I and TGF-β1 protein expression in the kidneys. In addition, decreased malondialdehyde levels and increased superoxide dismutase activity in the plasma and kidney were observed after co-treatment with hesperidin or captopril. These findings suggest that hesperidin inhibits L-NAME-induced vascular and renal alterations in rats. The possible mechanism may be related to the suppression of the activation of the renin-angiotensin system and expression of TGF-β1, and reduction of oxidative stress.

Angiotensin-Converting Enzyme in Smooth Muscle Cells Promotes Atherosclerosis-Brief Report.

Angiotensin-converting enzyme (ACE) is present in many cell types of atherosclerotic lesions. This study determined whether ACE activity in endothelial and smooth muscle cells (SMCs), 2 major resident cell types of the aorta, contributes to hypercholesterolemia-induced atherosclerosis. All study mice were in low-density lipoprotein receptor(-/-) background. To determine the contribution of ACE on endothelial cells to atherosclerosis, female ACE floxed mice were bred to male Tie2-Cre transgenic mice. Endothelial cell-specific deletion of ACE significantly decreased serum ACE activity, but had no effect on systolic blood pressure and atherosclerosis. Because ACE protein is present on SMCs, the most abundant cell type of the aorta, we then determined whether ACE on SMCs contributes to atherosclerosis. ACE was depleted from SMCs by breeding female ACE floxed mice with male SM22-Cre transgenic mice. SMC-specific deficiency of ACE did not affect ACE activity in serum, but ablated its presence and activity in the aortic media. Although SMC-specific deficiency of ACE had no effect on systolic blood pressure, it significantly attenuated hypercholesterolemia-induced atherosclerosis in both male and female mice. These studies provide direct evidence that ACE derived from endothelial cells does not play a critical role in atherosclerosis. Rather, SMC-derived ACE contributes to atherosclerosis, independent of circulating ACE activity and blood pressure.

Arg972 Insulin receptor substrate-1 is associated with decreased serum angiotensin-converting enzyme 2 levels in acute myocardial infarction patients: in vivo and in vitro evidence

BackgroundActivation of the renin-angiotensin system (RAS) plays a critical role in the pathophysiology of myocardial infarction (MI) and the development of heart failure. Both angiotensin-converting enzyme 2 (ACE2) and insulin/insulin receptor substrate-1 (IRS-1) show cardioprotective effects after acute MI. The Arg972 IRS-1 polymorphism is associated with diminished activity of insulin. In the present study, we explored the association among Arg972 IRS-1, acute MI, and serum levels of ACE2.MethodsA total of 711 subjects, including 351 subjects with first-time acute MI and 360 subjects without a history of MI were genotyped for Arg972 IRS-1 polymorphism. Serum levels of ACE2 and MI severity scores were determined. Primary human cardiomyocytes with overexpression of wild type IRS-1 or Arg972 IRS-1 or knockdown of endogenous IRS-1 were exposed to normoxia and hypoxia, and the expression levels of ACE2 were determined.ResultsThe serum ACE2 level was significantly increased in acute MI patients compared with that of non-MI controls. Compared with wild type IRS-1 carriers, Arg972 IRS-1 carriers exhibited decreased serum ACE2 levels and increased MI severity scores after MI. Our in vitro data demonstrate that impairment of insulin/IRS-1/PI3K signaling by overexpression of Arg972-IRS-1, knockdown of endogenous IRS-1, or PI3K inhibitor can abolish hypoxia-induced IRS-1-associated PI3K activity and ACE2 expression in human cardiomyocytes, which suggests a causal relationship between Arg972-IRS-1 and decreased serum ACE2 levels in acute MI patients. Our in vitro data also indicate that insulin/IRS-1/PI3K signaling is required for ACE2 expression in cardiomyocytes, and that hypoxia can enhance the induction effect of insulin/IRS-1/PI3K signaling on ACE2 expression in cardiomyocytes.ConclusionsThis study provides the first evidence of crosstalk between insulin/IRS-1/PI3K signaling and RAS after acute MI, thereby adding fresh insights into the pathophysiology and treatment of acute MI.

Comparing Effects of Carbohydrate (CHO) Blockers and Trivalent Chromium on CHO-Induced Insulin Resistance and Elevated Blood Pressure in Rats

Objective: In Sprague-Dawley rats (SD), we compared two categories of natural dietary supplements that influence carbohydrate (CHO) metabolism via different basic mechanisms to ameliorate insulin resistance (IR) and elevated blood pressure (BP) associated with heavy sugar/starch consumption. Two dietary supplements (bean extract and l-arabinose) are often referred to as carb blockers (CBs), because they slow the gastrointestinal absorption of CHO. Trivalent chromium (CR) falls into a group of so-called insulin sensitizers, because its major effect is to enhance peripheral insulin sensitivity. Method: We divided 48 mature male SD into 4 groups of 12. The first group received powdered baseline diet alone (Con). The remaining 3 SD groups (groups 2–4) ingested regular rat chow containing 20% w/w sucrose and 20% w/w rice starch. The second group received only this CHO-enriched chow. To the high-CHO diets of the remaining two groups, either CB to slow CHO absorption (CHO + CB) (group 3) or an insulin sensitizer, trivalent CR (CHO + CR; group 4), was added. Results: Compared to Con group 1, adding high CHO content to the diet of group 2 significantly increased circulating glucose levels and systolic BP (SBP). Addition of CB or CR to the feed of groups 3 and 4 overcame the perturbations that occurred with high CHO challenge in group 2; that is, they lowered circulating glucose concentrations to Con levels, enhanced response to exogenous insulin, and overcame the gradual elevation of SBP. Compared to group 2, the two treatment groups (3 and 4) also showed decreased renin–angiotensin system activity, decreased serum angiotensin-converting enzyme activity, and enhanced nitric oxide activity. Conclusions: Our data indicate that high doses of CB and CR, despite their different mechanisms of action, can completely overcome CHO-induced IR and BP elevations. The data further suggest that CB and CR affect only the changes brought on by heavy CHO ingestion, because IR and SBP in groups 3 and 4 mirrored Con values (group 1), never producing values lower than baseline. Earlier use of CB and CR in the life cycle appears more effective in overcoming CHO-induced perturbations than later use.

Carvedilol Prevents Ovariectomy-Induced Myocardial Contractile Dysfunction in Female Rat

Carvedilol has beneficial effects on cardiac function in patients with heart failure but its effect on ovariectomy-induced myocardial contractile dysfunction remains unclear. Estrogen deficiency induces myocardial contractile dysfunction and increases cardiovascular disease risk in postmenopausal women. Our aim was to investigate whether carvedilol, a beta receptor blocker, would prevent ovariectomy-induced myocardial contractile dysfunction. Female rats (8 weeks old) that underwent bilateral ovariectomy were randomly assigned to receive daily treatment with carvedilol (OVX+CAR, 20 mg/kg), placebo (OVX) and SHAM for 58 days. Left ventricle papillary muscle was mounted for isometric tension recordings. The inotropic response to Ca2+ (0.62 to 3.75 mM) and isoproterenol (Iso 10−8 to 10−2 M) were assessed. Expression of calcium handling proteins was measured by western blot analysis. Carvedilol treatment in the OVX animals: prevented weight gain and slight hypertrophy, restored the reduced positive inotropic responses to Ca2+ and isoproterenol, prevented the reduction in SERCA2a expression, abolished the increase in superoxide anion production, normalized the increase in p22phox expression, and decreased serum angiotensin converting enzyme (ACE) activity. This study demonstrated that myocardial contractile dysfunction and SERCA2a down regulation were prevented by carvedilol treatment. Superoxide anion production and NADPH oxidase seem to be involved in this response.

Interaction of A-240T and A2350G related genotypes of angiotensin-converting enzyme (ACE) is associated with decreased serum ACE activity and blood pressure in a healthy Iranian population

Most of renin–angiotensin system (RAS) gene polymorphisms have not yet been studied in the Iranian population. In the present study, the frequencies of common polymorphisms in the RAS genes, including angiotensin-converting enzyme (ACE) insertion/deletion (I/D) and three single-nucleotide polymorphisms (SNPs), i.e., A-240T, T-93C and A2350G, angiotensinogen M235T, angiotensin II receptor type 1 A1166C and angiotensin II receptor type 2 C3123A variants were determined in DNAs extracted from venous blood of 104 healthy Iranian volunteers. Genotyping was performed by PCR-RFLP method. Serum ACE activity was also assayed using reverse phase HPLC. Combined polymorphisms of TT (A-240T) and GG (A2350G) was significantly associated with decreased serum ACE activity (P=0.042) and decreased diastolic blood pressure (P=0.040). The angiotensin II receptor type 1 A1166C polymorphism (CC genotype) showed a significant association with declined diastolic blood pressure (P=0.028). Serum ACE activity was significantly higher in men compared to women (P=0.033). ACE activity also showed a direct association with diastolic blood pressure (P<0.001). No association was obtained among each single polymorphism with body mass index (BMI), fasting blood sugar (FBS), lipid profile and ACE activity. In conclusion, combined polymorphisms of A-240T and A2350G seem to affect serum ACE level as well as diastolic blood pressure in our study population. However, it also might be hypothesized that they are in strong linkage disequilibrium with other functional mutations not studied yet. Our findings revealed that gene interactions can play an important role in various biological conditions.

Prognostic value of serum angiotensin-converting enzyme activity for outcome of community-acquired pneumonia

In a previous study, a relation between decreased serum angiotensin-converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community-acquired pneumonia. This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004-2006; n=157 and 2007-2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups. A total of 265 patients were enrolled in this study. Mean age was 60±19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (≥20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57-9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality. This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia.

Blood pressure lowering effects of niacin-bound chromium(III) (NBC) in sucrose-fed rats: Renin–angiotensin system

Excessive intake of sugars significantly elevates systolic blood pressure (SBP) in susceptible rats. Although the exact pathological mechanisms behind sugar-induced hypertension are uncertain and may be multiple, disturbances in the renin–angiotensin system (RAS) manifested by elevated circulating levels of angiotensin-2 may be involved. We attempted to confirm that the RAS was significantly involved in sugar-induced BP elevations and examined whether the ability of niacin-bound chromium (NBC) to ameliorate sugar-induced SBP elevations was due, at least in part, through effects on the RAS. Initially, 40 mature Sprague-Dawley rats (SD), male and female, were involved in the study comparing two methods to estimate rat blood pressure indirectly. Then 13 were selected to examine the effects of NBC on the RAS. All rats eventually ingested a diet heavy in sucrose (30%w/w). In addition to blood pressure readings, the following procedures were implemented: insulin and losartan challenges, evaluation of serum ACE activity, measurement of serum angiotensin-2 levels, blood chemistries, and LNAME challenge. While dietary sucrose raised SBP significantly in control, adding NBC to the treatment group lowered it back toward baseline. The treatment group was more sensitive to exogenous insulin challenge and showed decreased activity of the RAS estimated by less lowering of SBP after losartan challenge, decreased serum ACE (angiotensin-converting enzyme) activity, and lower levels of circulating angiotensin-2. The former two parameters showed statistical significance; and the latter, a trend toward statistical significance. A separate group receiving captopril served as a positive control and showed decreased ACE activity and circulating levels of angiotensin-2 compared to the control group. Our data suggest that the RAS plays a significant role in sugar-induced hypertension and that NBC lowers SBP, at least in part, via actions on the RAS. Other findings suggest that the NO system is important in sucrose-induced BP elevations as well.

Attenuation of Vascular/Neural Dysfunction in Zucker Rats Treated With Enalapril or Rosuvastatin

Obese Zucker rats, animal model for the metabolic syndrome, develop a diabetes-like neuropathy that is independent of hyperglycemia. The purpose of this study was to determine whether drugs used to treat cardiovascular dysfunction in metabolic syndrome also protect nerve function. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with enalapril or rosuvastatin. Lean rats were used as controls. Vasodilation in epineurial arterioles was measured by videomicroscopy. Endoneurial blood flow (EBF) was measured by hydrogen clearance and nerve conduction velocity was measured following electrical stimulation of motor or sensory nerves. Enalapril treatment decreased serum angiotensin-converting enzyme (ACE) activity and both drugs reduced serum cholesterol levels. In obese Zucker rats at 32 weeks of age superoxide levels were elevated in the aortas and epineurial arterioles, which were reduced by treatment with either drug. Nitrotyrosine levels were increased in epineurial arterioles and reduced with enalapril treatment. EBF was decreased and corrected by treatment with either drug. Motor nerve conduction velocity was decreased and significantly improved with enalapril treatment. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and this was significantly improved with either treatment. Treatment with either enalapril or rosuvastatin significantly reversed the decrease in acetylcholine-mediated vascular relaxation of epineurial arterioles in obese Zucker rats. Even though obese Zucker rats have normal glycemia vascular and neural dysfunctions develop with age and can be improved by treatment with either enalapril or rosuvastatin.

Angiotensin-converting enzyme (ACE) I/D corrected serum ACE activity and severity assessment of community-acquired pneumonia

Various studies have described decreased serum angiotensin-converting enzyme (ACE) activity in patients with pneumonia. The aim of the present study was to evaluate the role of ACE in pneumonia by comparing ACE insertion/deletion (I/D) genotype corrected serum ACE activity and to establish whether the severity of the disease correlates with lower ACE activity. This was a prospective hospital-based observational study including 134 patients with pneumonia. Serum ACE activity was determined at admission, on days 2, 3, 5 and 10 of hospital stay, and at recovery. Based on ACE genotype and reference values, corresponding Z-scores were calculated. Disease severity, quantified by the acute physiology score (APS), and clinical outcome were compared between tertile groups of the Z-scores. A significant decrease in serum ACE activity during an episode of pneumonia with return to control range during recovery was observed for all three genotypes (II, ID and DD). The calculated Z-scores showed a negative correlation with APS scores (p=0.050). No significant association between decreased serum ACE activity and clinical outcome was observed. Serum ACE activity is significantly decreased during the acute phase of pneumonia. Despite correction for ACE I/D genotype, decreased ACE activity did not show a prognostic value. Further studies are needed to examine the mechanisms behind and diagnostic value of decreased ACE activity in community-acquired pneumonia.

Comparison of Acute Cardiovascular Effects of Cadmium and Captopril in Relation to Oxidant and Angiotensin Converting Enzyme Activity in Rats

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 ± 0.02 nmol/mL as compared to 0.12 ± 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P<0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P<0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 ± 1.1 U/mL (control levels 10.7 ± 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.

Long-Term Treatment With Perindopril Ameliorates Dobutamine-Induced Myocardial Ischemia in Patients With Coronary Artery Disease

The present study was designed to examine whether long-term blockade of angiotensin-converting enzyme (ACE) with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease (CAD). Twelve patients with proven CAD were randomly divided in two groups; one group received perindopril (8 mg/day, p.o.) for 3 months and another group served as a control. To evaluate anti-ischemic effects of perindopril, dobutamine stress echocardiography was performed before and 3 months after the treatment in a double-blind manner. Long-term treatment with perindopril significantly ameliorated the dobutamine-induced myocardial ischemia, as evaluated by time to the onset of symptoms, magnitude of electrocardiographic ST-segment changes, and left ventricular wall motion score (all P<0.05). The treatment significantly decreased serum ACE activities (P<0.01) and increased plasma bradykinin concentrations (P<0.05). The extent of reduction of left ventricular wall motion score by perindopril was closely correlated with that of inhibition of serum ACE activities (P<0.01) and with that of increase in plasma bradykinin concentrations (P<0.05). By contrast, no such beneficial changes were noted in the control group. These results provide the first evidence that long-term treatment with perindopril exerts anti-ischemic effects on the myocardial ischemia induced by increased myocardial oxygen demand in patients with CAD.

Angiotensin-converting enzyme and anorexia nervosa.

Angiotensin-converting enzyme (ACE) activity was measured in 10 patients with anorexia nervosa, 6 with hyperthyroid Graves' disease, and 7 with primary hypothyroidism. Patients with anorexia nervosa had a low serum ACE activity (9.8 +/- 2.2 IU/l), as compared to findings in normal subjects (13.4 +/- 3.5 IU/l) (P less than 0.05). Patients with hyperthyroid Graves' disease had high serum ACE activity (23.7 +/- 5.8 IU/l), as compared to levels in normal subjects (P less than 0.01), and patients with primary hypothyroidism tended to have low serum ACE activity (10.1 +/- 1.8 IU/l), compared to the normal subjects (P less than 0.1). Following weight gain (before; 71.3 +/- 10.2% of ideal body weight, after; 88.7 +/- 5.6% of ideal body weight), serum ACE activity in patients with anorexia nervosa reverted to within the normal range (13.8 +/- 3.5 IU/l), and serum T3 concentration was restored to the normal range (before; 0.7 +/- 0.2 ng/ml, after; 1.1 +/- 0.3 ng/ml). In these patients, ACE activity correlated with the per cent of ideal body weight (P less than 0.05). These data suggest that, in underweight subjects with anorexia nervosa, decreased serum ACE activities may relate to emaciation.

Prolonged reduction in serum angiotensin converting enzyme activity after treatment of rabbits with bleomycin

Previous work from this laboratory ( J. S. Lazo, J. D. Catravas, and C. N. Gillis, Biochem. Pharmacol. 30, 2577–2584, 1981; J. D. Catraveras, J. S. Lazo, and C. N. Gillis, J. Pharmacol. Exp. Ther. 217, 524–529, 1981) demonstrated that subacute bleomycin (BLM) administration (5 mg/kg) to rabbits three times weekly for 4 weeks produced a marked decrease in serum angiotensin converting enzyme (ACE) activity in addition to producing both morphological and biochemical evidence of pulmonary endothelial damage. In this work, the reversibility of the decreased serum ACE activity and the biochemical and morphological status of the pulmonary endothelium after a substantial drug-free period in rabbits was examined. Rabbits were injected sc three times weekly for 4 weeks with vehicle or BLM (5 mg/kg) and then maintained drug free for an additional 6 or 7 weeks. Serum ACE activity decreased over 60% during the BLM treatment but did not return to control levels at any time during the drug-free period. The pulmonary endothelium, however, appeared undamaged. No decrease in pulmonary ACE activity was detected either in vitro or in vivo nor was the single-pass pulmonary removal in vivo of [ 3H]norepinephrine and 5-[ 14C]hydroxytryptamine different between BLM-treated and control rabbits after the drug-free period. In addition, no evidence of pulmonary endothelial damage was observed by ligh and electron microscopy. Thus, reduction in serum ACE activity appears to be a durable reflection of BLM toxicity in rabbits that persists even in the absence of any detectable biochemical or morphologic endothelial injury.

Decreased serum angiotensin converting enzyme in adult respiratory distress syndrome associated with sepsis: a preliminary report.

Serum angiotensin converting enzyme (ACE) levels were obtained in 24 control patients who were critically ill, in 11 patients with cardiogenic pulmonary edema, in 8 patients with status postcardiopulmonary bypass, and in 12 patients with adult respiratory distress syndrome (ARDS). Mean values in cardiogenic pulmonary edema (24.3 +/- 3.9 SD) in cardiopulmonary bypass (19.5 +/- 3.1) and in patients with ARDS and no sepsis (n = 7, 19.0 +/- 5.5) were not significantly different from controls (20.7 +/- 2.8). In contrast, patients with ARDS and sepsis had markedly decreased serum ACE levels which fell outside of control range (n = 5, 8.6 +/- 2.3). The authors speculate that decreased ACE levels in the combination of sepsis and ARDS are due to the presence of circulating inhibitors of ACE. The finding of decreased serum ACE can be of potential clinical usefulness by raising the possibility of sepsis as the etiology of ARDS before results of blood cultures are available.