Although Angiotensin-converting Enzyme Research Articles

Oral angiotensin-converting enzyme inhibitor captopril protects the heart from Porphyromonas gingivalis LPS-induced cardiac dysfunction in mice.

Although angiotensin converting enzyme (ACE) inhibitors are considered useful for the treatment of human heart failure, some experimental failing-heart models have shown little beneficial effect of ACE inhibitors in animals with poor oral health, particularly periodontitis. In this study, we examined the effects of the ACE inhibitor captopril (Cap; 0.1 mg/mL in drinking water) on cardiac dysfunction in mice treated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS) at a dose (0.8 mg/kg/day) equivalent to the circulating level in patients with periodontal disease. Mice were divided into four groups: 1) Control, 2) PG-LPS, 3) Cap, and 4) PG-LPS + Cap. After1 week, we evaluated cardiac function by echocardiography. The left ventricular ejection fraction was significantly decreased in PG-LPS-treated mice compared to the control (from 66 ± 1.8 to 59 ± 2.5%), while Cap ameliorated the dysfunction (63 ± 1.1%). The area of cardiac fibrosis was significantly increased (approximately 2.9-fold) and the number of apoptotic myocytes was significantly increased (approximately 5.6-fold) in the heart of PG-LPS-treated group versus the control, and these changes were suppressed by Cap. The impairment of cardiac function in PG-LPS-treated mice was associated with protein kinase C δ phosphorylation (Tyr-311), leading to upregulation of NADPH oxidase 4 and xanthine oxidase, and calmodulin kinase II phosphorylation (Thr-286) with increased phospholamban phosphorylation (Thr-17). These changes were also suppressed by Cap. Our results suggest that the renin-angiotensin system might play an important role in the development of cardiac diseases induced by PG-LPS.

Combined angiotensin-converting enzyme and aminopeptidase inhibition for treatment of experimental ventilator-induced lung injury in mice.

Introduction: Ventilator-induced lung injury (VILI) may aggravate critical illness. Although angiotensin-converting enzyme (ACE) inhibition has beneficial effects in ventilator-induced lung injury, its clinical application is impeded by concomitant hypotension. We hypothesized that the aminopeptidase inhibitor ALT-00 may oppose the hypotension induced by an angiotensin-converting enzyme inhibitor, and that this combination would activate the alternative renin-angiotensin system (RAS) axis to counteract ventilator-induced lung injury. Methods: In separate experiments, C57BL/6 mice were mechanically ventilated with low (LVT, 6mL/kg) and high tidal volumes (HVT, 30mL/kg) for 4h or remained unventilated (sham). High tidal volume-ventilated mice were treated with lisinopril (0.15μg/kg/min) ± ALT-00 at 2.7, 10 or 100μg/kg/min. Blood pressure was recorded at baseline and after 4h. Lung histology was evaluated for ventilator-induced lung injury and the angiotensin (Ang) metabolite profile in plasma (equilibrium levels of Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5) was measured with liquid chromatography tandem mass spectrometry at the end of the experiment. Angiotensin concentration-based markers for renin, angiotensin-converting enzyme and alternative renin-angiotensin system activities were calculated. Results: High tidal volume-ventilated mice treated with lisinopril showed a significant drop in the mean arterial pressure at 4h compared to baseline, which was prevented by adding ALT-00 at 10 and 100μg/kg/min. Ang I, Ang II and Ang 1-7 plasma equilibrium levels were elevated in the high tidal volumes group versus the sham group. Lisinopril reduced Ang II and slightly increased Ang I and Ang 1-7 levels versus the untreated high tidal volumes group. Adding ALT-00 at 10 and 100μg/kg/min increased Ang I and Ang 1-7 levels versus the high tidal volume group, and partly prevented the downregulation of Ang II levels caused by lisinopril. The histological lung injury score was higher in the high tidal volume group versus the sham and low tidal volume groups, and was attenuated by lisinopril ± ALT-00 at all dose levels. Conclusion: Combined angiotensin-converting enzyme plus aminopeptidase inhibition prevented systemic hypotension and maintained the protective effect of lisinopril. In this study, a combination of lisinopril and ALT-00 at 10μg/kg/min appeared to be the optimal approach, which may represent a promising strategy to counteract ventilator-induced lung injury that merits further exploration.

Adverse Effects of Angiotensin-Converting Enzyme Inhibitors in Humans: A Systematic Review and Meta-Analysis of 378 Randomized Controlled Trials.

Background: Although angiotensin-converting enzyme (ACE) inhibitors are among the most-prescribed medications in the world, the extent to which they increase the risk of adverse effects remains uncertain. This study aimed to systematically determine the adverse effects of ACE inhibitors versus placebo across a wide range of therapeutic settings. Methods: Systematic searches were conducted on PubMed, Web of Science, and Cochrane Library databases. Randomized controlled trials (RCTs) comparing an ACE inhibitor to a placebo were retrieved. The relative risk (RR) and its 95% confidence interval (95% CI) were utilized as a summary effect measure. A random-effects model was used to calculate pooled-effect estimates. Results: A total of 378 RCTs fulfilled the eligibility criteria, with 257 RCTs included in the meta-analysis. Compared with a placebo, ACE inhibitors were associated with an significantly increased risk of dry cough (RR = 2.66, 95% CI = 2.20 to 3.20, p < 0.001), hypotension (RR = 1.98, 95% CI = 1.66 to 2.35, p < 0.001), dizziness (RR = 1.46, 95% CI = 1.26 to 1.70, p < 0.001), and hyperkalemia (RR = 1.24, 95% CI = 1.01 to 1.52, p = 0.037). The risk difference was quantified to be 0.037, 0.030, 0.017, and 0.009, respectively. Conclusions: We quantified the relative risk of numerous adverse events associated with the use of ACE inhibitors in a variety of demographics. This information can help healthcare providers be fully informed about any potential adverse consequences and make appropriate suggestions for their patients requiring ACE inhibitor therapy.

Clinical effect of nonsteroidal mineralocorticoid receptor (MR) antagonists in the treatment of diabetic kidney disease: expectations as a new therapeutic strategy

Diabetes mellitus is the main cause of chronic kidney disease (CKD) in Japan and worldwide. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) are basic drugs for the treatment of CKD with diabetes (diabetic kidney disease, DKD) with albuminuria and/or proteinuria, it has also become clear that the use of an ACE inhibitor or ARB alone is not fully sufficient. We have previously reported the clinical effects of mineralocorticoid receptor (MR) antagonists and recommended their use in addition to renin-angiotensin system inhibitors. Recently, new types of nonsteroidal MR antagonists have been developed, and the results of a large-scale study are expected. Nonsteroidal MR antagonists are distributed in the heart, lungs, liver, and kidneys when administered orally and are characterized by their equivalent distribution between the heart (nonepithelial tissue) and kidneys (epithelial tissue). We summarize the latest evidence regarding the use of nonsteroidal MR antagonists in the treatment of DKD. Hyperkalemia and renal dysfunction are frequent during MR antagonist treatment. However, with careful and combined monitoring of these two conditions, the effectiveness of MR antagonists will not be diminished; conversely, it is apparent that patients at such risk will benefit more from the addition of an MR antagonist to the treatment regimen. The most important measure against hyperkalemia is the regular monitoring of serum potassium levels and renal function. The safest and most reliable measure against hyperkalemia is the combined use of a new oral potassium adsorbent that has high potassium selectivity and few side effects. In DKD treatment, it is important to continue using MR antagonists without interruption as much as possible.

Role of Neuron-Specific Enolase in the Diagnosis and Disease Monitoring of Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. The diagnosis of sarcoidosis is based on clinicopathologic findings accompanied by the formation of granulomas in multiple organs, including the lung. Although angiotensin-converting enzyme (ACE) and soluble interleukin 2 receptor (sIL-2R) are traditionally used for the diagnosis of sarcoidosis, specific diagnostic markers remain to be determined. In the current study, we found that serum neuron-specific enolase (NSE) levels were elevated in patients with sarcoidosis. Serum NSE levels were positively correlated with serum ACE and sIL-2R levels. The sensitivity of NSE alone was modest, but its combination with sIL-2R and ACE had the highest sensitivity compared to those of each single marker. When comparing serum NSE and pro-gastrin-releasing peptide (ProGRP) levels in SCLC patients with those in patients with sarcoidosis and nonsarcoidotic benign diseases, serum NSE could be used to distinguish SCLC from sarcoidosis and nonsarcoidosis by setting at a cutoff value of 17.0 ng/ml with a sensitivity of 73.5% and a specificity of 90.2%, which were comparable to those of ProGRP. Serum NSE levels were associated with organ involvement and were higher in sarcoidosis patients who had been treated with oral corticosteroid (OCS) than in those who had never received OCS therapies; there was a positive association between elevated serum NSE levels and OCS use. Increased concentrations of serum NSE in patients at the nonremission phase decreased after spontaneous remission, whereas serum NSE levels fluctuated in accordance with serum ACE or sIL-2R levels during the follow-up period in patients with sarcoidosis. These findings suggest that NSE could be a marker for the diagnosis and monitoring of the clinical outcome of patients with sarcoidosis.

A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment

Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment.

Clinical Summaries

Clinical Summaries

Pharmacological management of hypertension

Hypertension is a major risk factor for cardiovascular disease, and is both common and amenable to treatment. Several major new studies have appeared recently and in response the National Institute for Health and Clinical Excellence and the British Hypertension Society have collaborated to update their respective guidelines on primary hypertension, and to agree joint recommendations. The update focuses only on pharmacological aspects of treatment. Wherever possible, the recommendations are based on the clinical outcomes of mortality, stroke, myocardial infarction, heart failure, and new onset diabetes mellitus, rather than on blood pressure lowering. A brief treatment algorithm is included. In summary, either calcium channel inhibitors or thiazide-type diuretics should be the preferred initial agent for use in primary hypertension in most patients, although angiotensin converting enzyme (ACE) inhibitors (including angiotensin-II receptor inhibitors if ACE-intolerant) are preferred in patients younger than 55.

Major Congenital Malformations After First-Trimester Exposure to ACE Inhibitors

ABSTRACT Although angiotensin-converting enzyme (ACE) inhibitors are avoided in the second and third trimesters of pregnancy because of an increased risk of fetal pathology, adverse fetal outcomes have not been related to first-trimester exposure. For the most part, however, evidence that exposure early in pregnancy is safe comes from a limited number of animal studies and case report analyses. This cohort study included 29,507 infants enrolled in Medicaid in Tennessee who were born in the years 1985 to 2000 and for whom there was no evidence of maternal diabetes. A total of 411 infants had been exposed to some kind of antihypertensive medication only in the first trimester: 209 infants had been exposed to ACE inhibitors and 202 were exposed to other antihypertensive drugs. Among the 202 infants exposed to other antihypertensive agents in the first trimester, the risk of any major congenital malformation was not increased. Of the 209 infants exposed to ACE inhibitors in the first trimester, 18 had major congenital malformations (8.6%); the adjusted proportion was 7.1%. Seven of these 18 infants had multiple malformations, but 5 of the 7 had been exposed in the second trimester as well and 3 had been exposed in all 3 trimesters. The risk ratio (RR) for first-trimester exposure, compared with children not exposed to any type of antihypertensive drug, was 2.71 (95% confidence interval [CI], 1.72–4.27). This RR was the result of an increased number of cardiovascular malformations (n = 8; RR, 3.72; 95% CI, 1.89–7.30) and central nervous system malformations (n = 3; RR, 4.39; 95% CI, 1.37–14.02). Other malformations included renal dysplasia (n = 2), hypospadius, intestinal and choanal atresia, Hirschsprung disease, and diaphragmatic hernia (n = 1 each). A post hoc analysis revealed a significantly increased risk of renal malformations (RR, 9.32; 95% CI, 1.79–48.5), but the risk of the other malformations was not significantly increased. Women of childbearing age, like other individuals, are increasingly being given ACE inhibitors as the indications for these drugs continue to expand. The present findings strongly suggest that these drugs should not be given to pregnant women during the first trimester.

Effect of spironolactone and captopril on nitric oxide and S-nitrosothiol formation in kidney of L-NAME-treated rats

Although angiotensin-converting enzyme (ACE) inhibitors are well-established drugs in the treatment of hypertension, they are not supposed to be sufficient in the inhibition of aldosterone formation. The present study analyzes the effect of aldosterone receptor antagonist, spironolactone and ACE inhibitor, captopril on nitric oxide (NO) and S-nitrosothiol formation in the kidney of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Male Wistar rats were divided into six groups: (1) controls, (2) L-NAME (40 mg/kg/day), (3) spironolactone (200 mg/kg/day), (4) captopril (100 mg/kg/day), (5) L-NAME+spironolactone, and (6) L-NAME+captopril. After 4 weeks, NO synthase (NOS) activity, protein expression of endothelial NOS, inducible NOS and concentration of thiol and S-nitrosothiol groups were determined in the kidney. Besides the increase in systolic blood pressure (by 32%) and the decrease in NOS activity (by 37%), L-NAME treatment lowered the concentration of thiols (by 32%) and S-nitrosothiols (by 36%) in the renal tissue. Simultaneous treatment with spironolactone preserved NOS activity and S-nitrosothiols on the control level, whereas captopril did not affect these parameters modified by L-NAME treatment. Moreover, spironolactone increased expression of endothelial NOS protein without affecting inducible NOS protein expression. In conclusion, both captopril and spironolactone prevented L-NAME-induced hypertension and the decline of the antioxidant potential of the kidney tissue. However, only spironolactone improved NOS activity which led to the S-nitrosothiols formation. Both NO itself and S-nitrosothiols may contribute to the preventive effect of spironolactone against development of L-NAME-induced hypertension.

Improving Outcomes in Post–Acute Myocardial Infarction Heart Failure: Incorporation of Aldosterone Blockade into Combination Therapy to Optimize Neurohormonal Blockade

Although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and beta-blockers have been proved to reduce mortality in patients with heart failure post-acute myocardial infarction (AMI), studies show that these agents are consistently underused in this population. Further, morbidity and mortality remain high even when standard-of-care therapies are applied. Thus, new strategies have been sought to better counteract the maladaptive effects of neurohormonal stimulation in post-AMI heart failure. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone, when used in addition to standard therapy, results in significant incremental improvements in survival and morbidity and is safe and well tolerated in this setting. Based on this, major therapeutic guidelines in the United States and Europe now strongly recommend that all eligible patients with concomitant heart failure post-AMI be treated with an aldosterone blocker in addition to an ACE inhibitor (or an ARB) and a beta-blocker. To achieve needed improvements in outcomes in this population, early and consistent initiation of these evidence-based, guideline-recommended therapies in all eligible patients is crucial.

Antagonists of Aldosterone and Proteinuria in Patients With CKD: An Uncontrolled Pilot Study

Experimental evidence suggests that aldosterone may contribute to progressive kidney disease. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 receptor antagonists (ARBs) suppress the renin-angiotensin system, these agents do not adequately control plasma aldosterone levels. Hence, administration of aldosterone receptor antagonists may provide additional renal benefits to the ACE inhibitors and ARBs. In the present uncontrolled pilot study, we evaluate the short-term (8 weeks) effects of spironolactone on proteinuria in 42 patients with chronic kidney disease (CKD) already treated with ACE inhibitors and/or ARBs. Spironolactone (25 mg/d for 8 weeks) decreased proteinuria from protein of 2.09 +/- 0.16 to 1.32 +/- 0.08 g/24 h after 2 weeks and 1.05 +/- 0.08 g/24 h after 8 weeks. Four weeks after discontinuation of spironolactone therapy, proteinuria returned to close to baseline values. Baseline proteinuria correlated significantly with plasma aldosterone level (r = 0.81; P < 0.0001). Moreover, baseline aldosterone level correlated significantly with degree of reduction in proteinuria after treatment with spironolactone (r = 0.70; P < 0.0001). Spironolactone caused a significant increase in serum potassium levels (from 4.4 +/- 0.1 mEq/L [mmol/L] at baseline to 4.8 +/- 0.1 mEq/L [mmol/L] after 8 weeks of treatment; P < 0.01). This study shows that spironolactone may effectively reduce proteinuria in patients with CKD. Concerns remain in regard to the risk for hyperkalemia in patients with CKD. Prospective randomized trials are necessary to confirm the efficacy and safety of antagonists of aldosterone on proteinuria and progression of CKD.

ACE Inhibitors and Chronotherapy

Chronotherapy can improve the effectiveness and reduce the adverse reactions of drugs and actually is used for several conditions including cardiovascular diseases. Although angiotensin converting enzyme (ACE) inhibitors are available for the therapy of patients with hypertension and/or heart failure, these agents have some characteristic adverse effects such as angioedema and dry cough. It has been reported that the dosing of ACE inhibitor at an inactive period has a better protective effect against cardiac hypertrophy in hypertensive rats, and changing dosing time from morning to evening reduces the severity and frequency of the drug-induced dry cough of hypertensive patients treated in the morning. Thus, the dosing of ACE inhibitors in the inactive span is more effective and safe. Dosing in the evening may be an alternative for hypertensives with dry cough with a morning dose of ACE inhibitors, if one ascertains that no circadian hyperamplitude tension is induced by the evening dose of this or any other antihypertensive drug.

Angiotensin-Converting Enzyme Inhibitor Use in Elderly Patients Hospitalized with Heart Failure and Left Ventricular Systolic Dysfunction

Purpose: Although angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with systolic heart failure, prior studies suggest that elderly cohorts are less likely to receive such therapy. The purpose of this study was to determine the age dependence of adherence to guideline-based medical care in hospitalized heart failure patients. Methods: We performed a multicenter observational cohort study including 613 patients admitted to participating hospitals with a primary diagnosis of heart failure with ejection fraction ≤40%. This cohort was divided into four age groups (group 1: <60, group 2: 60–69, group 3: 70–79, and group 4: 80 years) and adherence to guideline-based medical care was measured. Results: ACE inhibitors were administered to 83% of ideal heart failure patients, and this rate was similar for all age groups. Elderly patients received significantly lower ACE inhibitor dosages compared to their younger counterparts (168, 148, 125 and 117 mg captopril in groups 1, 2, 3, and 4, respectively, p = 0.001). Lower creatinine clearance (p < 0.001), prior residence in a long-term care facility (p = 0.037), intolerance to ACE inhibitors (p = 0.006), lower blood pressure (p = 0.005), absence of a history of hypertension (p = 0.005), and no prior heart failure hospitalizations within the past year (p = 0.001) were found to be independent predictors of low ACE inhibitor dosing. Conclusions: In this heart failure benchmarking project, elderly patients received guideline-based ACE inhibitor therapy at similar rates, but at lower doses, compared to their younger counterparts.

Is angiotensin-converting enzyme inhibitor useful in a Japanese population for secondary prevention after acute myocardial infarction? A final report of the Japanese Acute Myocardial Infarction Prospective (JAMP) study

Background Although angiotensin-converting enzyme (ACE) inhibitors have appeared to be useful for secondary prevention after acute myocardial infarction (AMI) in Western countries, that has not been confirmed in non-western countries. We investigated whether ACE inhibitors improve survival rates in patients who have survived an AMI in Japan. Methods A randomized controlled trial, the first non-pharmaceutical company-supported multicenter trial of a medication in Japan, was carried out in 48 institutions from 1993 to 2000. A total of 888 of 1163 patients with AMI were eligible for the full analysis set (FAS). The mean patient age was 62 years, and 78% of patients were men. Subjects were randomized to 2 groups; 422 received ACE inhibitors and 466 did not receive ACE inhibitors. The primary end point was combined cardiac events, which was defined as cardiac or non-cardiac death, recurrent non-fatal myocardial infarction, coronary revascularization, and hospitalization because of worsening angina or congestive heart failure. The mean follow-up period was 5.8 years. Results There were no significant differences in the 2 groups in baseline data. During the follow-up period, 3 patients were lost to follow-up. With Kaplan-Meier analysis, the annual rate of total cardiac events was 32% in both groups. After adjustment for clinical baseline data, ACE inhibitor administration was not revealed with Cox regression analysis to have a significant prognostic effect in our study. Conclusion We did not show a significant improvement in outcome with ACE inhibitor administration in subjects who survived after AMI in a Japanese study population. Further evaluations with a larger population or in subjects who are at a higher risk for AMI are necessary to confirm our findings.

Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction.

Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident. Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks. Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings' upregulation. This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.

Treatment of high-risk African American patients: left ventricular dysfunction, heart failure, renal disease, and postmyocardial infarction.

African Americans experience more mortality and morbidity from hypertension-related complications than other racial groups. Although angiotensin-converting enzyme (ACE) inhibitors have clearly been shown to reduce mortality and morbidity in hypertensive white patients with heart failure, renal dysfunction, stroke, and acute myocardial infarction, African American patients have been underrepresented in these trials. The lack of direct evidence of the benefit of ACE inhibitors in these individuals and the suggestion that ACE inhibitors are less efficacious in this group has resulted in a reluctance to use ACE inhibitors in African Americans. However, retrospective analyses in black patients with heart failure and a recent randomized clinical trial in African Americans with renal dysfunction suggest that a regimen based on ACE inhibitors is efficacious in this racial group. Although diuretics remain first-line therapy, data now suggest that ACE inhibitors provide additional benefit and should be considered for use in patients with high-risk complications regardless of race.

Eplerenone: a selective aldosterone receptor antagonist (SARA).

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors

Purpose: Pathologic remodeling of the extracellular matrix is a critical mechanism in the development and progression of abdominal aortic aneurysms (AAAs). Although angiotensin-converting enzyme (ACE) inhibitors are known to alter vascular wall remodeling in other conditions, their effects on AAAs are unknown. In this study we assessed the effect of ACE inhibitors in a rodent model of aneurysm development. Methods: Male Wistar rats underwent transient aortic perfusion with porcine pancreatic elastase, followed by treatment with one of three ACE inhibitors (captopril [CP], lisinopril [LP], or enalapril [EP]), an angiotensin (AT)1 receptor antagonist (losartan [LOS]), or water alone (9 rats in each group). Blood pressure and aortic diameter (AD) were measured before elastase perfusion and on day 14, with an AAA defined as an increase in AD (ΔAD) of more than 100%. The structural features of the aortic wall were examined by means of light microscopy. Results: Aneurysmal dilatation consistently developed within 14 days of elastase perfusion in untreated rats, coinciding with the development of a transmural inflammatory response and destruction of the elastic media (mean ΔAD, 223% ± 28%). All three ACE inhibitors prevented AAA development (mean ΔAD: CP, 67% ± 4%; LP, 18% ± 12%; and EP, 14% ± 3%; each P <.05 vs controls). ACE inhibitors also attenuated the degradation of medial elastin without diminishing the inflammatory response. Surprisingly, the aneurysm-suppressing effects of ACE inhibitors were dissociated from their effects on systemic hemodynamics, and LOS had no significant effect on aneurysm development compared with untreated controls (mean ΔAD, 186% ± 19%). Conclusion: Treatment with ACE inhibitors suppresses the development of elastase-induced AAAs in the rat. Although this is associated with the preservation of medial elastin, the mechanisms underlying these effects appear to be distinct from hemodynamic alterations alone or events mediated solely by AT1 receptors. Further studies are needed to elucidate how ACE inhibitors influence aortic wall matrix remodeling during aneurysmal degeneration. (J Vasc Surg 2001;33:1057-64.)

Cardioprotection with angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor antagonist is not abolished by nitric oxide synthase inhibitor in ischemia-reperfused rabbit hearts.

Although angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II type 1 (AT1) receptor antagonist can protect the myocardium against ischemia-reperfusion injury, the mechanisms of the effect have not yet been characterized at the cellular level. We here examined the effect of the combination of an ACE inhibitor, temocaprilat, an AT1 receptor antagonist, CV-11974 and/or a nitric oxide synthase inhibitor, L-NAME, on the myocardial metabolism and contraction during ischemia and reperfusion by using phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts. After normothermic 20 min global ischemia, postischemic reperfusion of 30 min was carried out. Twenty-one hearts were divided into three experimental groups consisting of 7 hearts each: a Tem+CV group perfused with a combination of temocaprilat and CV-11974; a Tem+CV+L-NAME group perfused with a combination of temocaprilat and CV-11974 plus L-NAME, and a control group. During ischemia, both the Tem+CV group and Tem+CV+L-NAME group showed a significant inhibition of the decrease in adenosine triphosphate (ATP) compared with the control group (p<0.01); the increase in ATP was 50+/-3%, 42+/-4%, and 19+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively. Both experimental groups also showed a significant inhibition of the increase in left ventricular end-diastolic pressure (LVEDP) compared with the control group (p<0.01). After postischemic reperfusion, the Tem+CV group and Tem+CV+L-NAME group again showed a significant improvement of ATP as compared with the control group (p<0.01); the increase in ATP was 73+/-3%, 64+/-3%, and 47+/-4% in the Tem+CV group, Tem+CV+L-NAME group, and control group, respectively, and a significant decrease of LVEDP as compared with the control group (p<0.01). There were no differences in ATP, or LVEDP during ischemia and reperfusion between the Tem+CV group and Tem+CV+ L-NAME group. In conclusion, the combination of temocaprilat and CV-11974 showed significant potential for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion. This beneficial effect was not dependent on NO synthase.