Beneficial Effects Of Angiotensin-converting Enzyme Inhibitors Research Articles

Bradykinin, angiotensin-(1–7), and ACE inhibitors: how do they interact?

The beneficial effect of ACE inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of ACE inhibitors that are independent of bradykinin hydrolysis, i.e. ACE–bradykinin type 2 (B 2) receptor ‘cross-talk’, resulting in B 2 receptor upregulation and/or more efficient activation of signal transduction pathways, as well as direct activation of bradykinin type 1 receptors by ACE inhibitors. This review critically reviews the current evidence for hydrolysis-independent bradykinin potentiation by ACE inhibitors, evaluating not only the many studies that have been performed with ACE-resistant bradykinin analogues, but also paying attention to angiotensin-(1–7), a metabolite of both angiotensin I and II, that could act as an endogenous ACE inhibitor. The levels of angiotensin-(1–7) are increased during ACE inhibition, and most studies suggest that its hypotensive effects are mediated in a bradykinin-dependent manner.

Potential adverse interaction between aspirin and Lisinopril in hypertensive rats

The potential clinical effect of aspirin (ASA) in patients treated with angiotensin converting enzyme (ACE) inhibitors is debatable. Several studies have suggested that ASA attenuates the beneficial effects of ACE inhibitors in hypertension, congestive heart failure (CHF) or coronary artery disease (CAD) and have questioned the safety of using ASA concomitantly with these agents. The present study aims to investigate the possible interaction between ASA and ACE inhibitor in hypertensive rats. Hypertension was induced in adult male Wistar rats using Methylprednisolone (MP) 20 mg/kg per week s.c. for 2 weeks. The systolic blood pressure (SBP) was measured by noninvasive BP technique. The effect of Lisinopril (LS) 15 mg/kg per day and that of combination of LS and ASA; 100 and 25 mg/kg per day p.o. was studied on hypertension induced by glucocorticoid. Concurrent ASA treatment with LS did not hinder the hypotensive effect of LS at either dose. However ASA 100 mg/kg per day caused mortality in animals and produced massive cardiac necrosis and renal damage as evident from histopathology. Treatment with ASA 25 mg/kg per day caused lower mortality with variable effects on cardiac and renal tissues. These results indicate that ASA attenuates the beneficial effects of ACE inhibitor on survival in hypertensive rats and this effect was more pronounced at higher dose of ASA.

ACE inhibitor intervention in Type 1 diabetes with low grade microalbuminuria.

Several clinical trials have consistently shown that antihypertensive treatment, particularly with angiotensin-converting enzyme inhibitors (ACE-I) reduces albuminuria in Type 1 diabetic patients. More recently, data on the beneficial effects of ACE-I on the preservation of glomerular filtration rate and renal ultrastructure have emerged. However, in general, these trials have recruited a wide spectrum of diabetics, including some patients with severe albuminuria. Thus, the question of the ideal stage at which to instigate what is likely to be lifelong therapy in young people still remains unanswered. Exercise is known to significantly increase both blood pressure (BP) and urinary albumin excretion (UAE), both of which are important determinants of progression of nephropathy in diabetes. Thus, it is possible that exercise may have an adverse effect on diabetic renal disease. The effects of ACE-I on exercise-BP and exercise-UAE in microalbuminuric Type 1 diabetic patients has not been examined in long-term placebo-controlled studies. In the second part of this two-part review, we examine the effects of the ACE-I, lisinopril, 20 mg o.d. for two years, in comparison with placebo, on UAE, 24-hour ambulatory BP, exercise-BP, exercise-UAE and renal haemodynamics in 22 patients with Type 1 diabetes and low-grade microalbuminuria. We further discuss the effects of ACE-I on nephropathy and other complications of diabetes.

Modifying cardiovascular risk in diabetes mellitus.

DIABETES mellitus affects an estimated 35 million people in the United States, and the disease prevalence is predicted to increase by nearly 200% in the next several decades. As a result, anesthesiologists will be confronted with an increasing population of patients undergoing anesthesia and surgery who are at risk for ischemic heart disease. Hyperglycemia Predicts Cardiovascular Risk Diabetes is a significant predictor of perioperative cardiovascular morbidity and mortality, but few studies have evaluated methods to modify this risk. Compelling evidence indicates that aggressive management of diabetes may substantially decrease the adverse consequences of myocardial ischemia and infarction. The direct impact of hyperglycemia on cardiovascular mortality in patients with and without diabetes is a central theme of current research, and several investigations conducted during the past 20 yr demonstrated that mortality resulting from acute myocardial infarction (AMI) is increased if blood glucose concentration is elevated at the time of hospital admission. 1 These findings were confirmed in a recent prospective analysis of 336 consecutive patients admitted with AMI. 2 One-year mortality was 9% for patients with AMI and normal admission blood glucose values. In contrast, patients with hyperglycemia (blood glucose concentrations of 121 15, 168 13, and 282 65 mg/dl) on admission demonstrated substantial increases (P 0.005) in mortality to 13, 30, and 44%, respectively. 2 The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial addressed the prognostic significance of hyperglycemia in patients with type 1 and 2 diabetes and AMI. 3 A nearly linear relationship between blood glucose concentration on admission and long-term mortality was observed in conventionally treated patients in this randomized clinical trial (mortality rates of 35, 40, and 55% at blood glucose concentrations of 235, 235–298, and 298 mg/dl, respectively). A direct relationship between fasting blood glucose concentration and the risk of sustaining a cardiovascular event (e.g., sudden cardiac death, AMI, or cerebrovascular accident) has been demonstrated in a meta-regression analysis of data from 20 studies involving more than 95,000 patients. 4 The risk associated with fasting blood glucose concentrations was linear and extended below the threshold used to define diabetes. A fasting blood glucose value of only 110 mg/dl was associated with an increased relative risk of a cardiovascular event. Similarly, the odds ratio of AMI was increased to 1.5, 3.4, and 6.0 at fasting blood glucose concentrations of approximately 90, 110, and greater than 115 mg/dl, respectively. 5 Another large cohort study indicated that glycosylated hemoglobin (HbA1c) concentration, but not the presence of diabetes, predicted an increase in mortality. 6 The risk of all-cause mortality increased by a factor of 1.46 for every 1% increase in HbA 1c when male patients with diabetes, those with HbA 1c concentrations greater than 7%, or patients with a history of heart disease or stroke were excluded from the multivariate regression model. Similarly, creatinine kinase concentrations were higher in patients with hyperglycemia admitted with AMI compared with those with normal blood glucose levels. 2 These data demonstrate a striking relationship

Does angiotensin-converting enzyme inhibition improve the energetic status of cardiac and skeletal muscles in heart failure induced by aortic stenosis in rats?

Recently, we have demonstrated that heart failure in rats is associated with a myopathy altering energy metabolism in different muscles, but the origin of this myopathy is still unknown. Here, we studied the possible involvement of increased angiotensin II (Ang II) by treatment with perindopril, an inhibitor of angiotensin-converting enzyme (ACE). The beneficial effects of ACE inhibition could result either from vasodilatation-induced cardiac unloading or from inhibition of the direct angiotensin action on the muscle cells. The model of aortic banding with persisting left ventricular (LV) overload where the cardiac unloading does not occur allows to distinguish between the two effects of ACE inhibition. Four months after aortic clipping (just before the treatment), echocardiographic study showed an impairment of the systolic function (decrease of the LV shortening by 30% and ejection fraction by 21%). Ten-week treatment with perindopril dramatically decreased Ang II plasma level but did not reduce LV hypertrophy though a significant decrease in right ventricular (RV) hypertrophy occurred. Perindopril did not improve alterations in activities of energy metabolism enzymes (creatine kinase, citrate synthase, cytochrome c oxidase, lactate dehydrogenase) either in ventricular or in skeletal (gastrocnemius) muscle. Similarly, ACE inhibition did not improve the main parameters of mitochondrial respiration in permeabilized muscle fibers. These data suggest that the generalized metabolic myopathy induced by the hemodynamic abnormalities conditioned by the continuous LV overload (aorta clipping) does not result from the increase in Ang II level per se. Correction of hemodynamic parameters and LV unloading seem to be the prerequisite for the improvement of muscle energy metabolism abnormalities.

Angiotensin II inhibition increases cellular glucose transport during reperfusion but not ischemia in pig hearts

Objective --To study whether ACE inhibition and AT-II receptor blockade modulates myocardial glucose uptake during ischemia and reperfusion. Design --We developed a method for in vivo sampling of large trans -myocardial tissue samples from beating pig hearts and in vitro measurement of sarcolemmal glucose transport, in a series of experiments in which hearts were exposed to stimuli (glucose-insulin and pacing) known to promote cellular glucose transport. In the subsequent study we compared three experimental groups: (i) ACE inhibition (ACE-I, n r = r 6): increasing oral doses of benazepril up to 40 r mg daily for 3 weeks, (ii) angiotensin II receptor antagonist (AT II-A, n r = r 7): increasing oral doses of valsartan up to 320 r mg for 3 weeks, (iii) control ( n r = r 7). Samples were harvested at baseline, following 20 r min of regional ischemia, and following 5 and 15 r min of reperfusion. The samples were incubated with 3-O-methylglucose (MeGlu), and cellular MeGlu uptake was measured. Results --Insulin-glucose, pacing, and ischemia increased cellular MeGlu transport two- to fourfold ( p r < r 0.001). Cellular MeGlu transport was increased in ACE-I and AT II-A animals during reperfusion ( p r < r 0.001), but not at baseline or during ischemia, compared with controls. Conclusion --Enhanced capacity for glucose transport during reperfusion may be a mechanism underlying the beneficial effects of ACE inhibition and AT II-antagonism in ischemic heart disease.

Angiotensin-converting enzyme inhibition in adult hypertensive rats: a stereological study of renal filtration surface area.

1. Angiotensin-converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High- and low-perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low-dose perindopril were still considered hypertensive. Neither low-dose nor high-dose perindopril treatment had any observable effect on glomerular number (23 876 +/- 1201 vs 26 240 +/- 1465 glomeruli/kidney, respectively) or volume (2.25 +/- 0.21 and 1.96 +/- 0.06 x 10-3 mm3, respectively) compared with controls (glomerular number 25866 +/- 1210 glomeruli/kidney; glomerular volume 2.24 +/- 0.21 x 10-3 mm3). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 +/- 550.9, 8699.7 +/- 427.6, 9081.9 +/- 453.6, 8830.2 +/- 521.2 and 8559.4 +/- 341.4 mm2 for SHR, SHR low-dose perindopril, SHR low-dose perindopril + B2 antagonist, SHR high-dose perindopril and SHR high-dose perindopril + B2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high-dose nor low-dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.

Effects of angiotensin-converting enzyme inhibition on changes in left ventricular myocardial creatine kinase system after myocardial infarction: their relation to ventricular remodeling and function.

We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on changes in the myocardial intracellular creatine kinase (CK) system in relation to left ventricular (LV) remodeling and function in heart failure after myocardial infarction (MI) in rats. We compared the findings at 4 weeks after MI to those at 12 weeks after MI. LV weight and chamber size were significantly increased and percent fractional shortening (%FS) was decreased in untreated MI rats compared with normal control animals both at 4 and 12 weeks after MI. Animals with MI and treated with the ACE inhibitor temocapril showed significantly reduced LV weight and chamber size and increased %FS compared with untreated MI rats at 12 weeks after MI, but not at 4 weeks after MI. At 4 weeks after MI, no significant changes were found in the total creatine and relative distribution of each CK isoenzyme in either the temocapril-treated or untreated animals with MI compared with the normal controls. In contrast, at 12 weeks after MI, untreated MI rats showed significant reductions in the total creatine and mitochondrial and MM-CK fractions and increases in the MB- and BB-CK fractions compared with the controls. The alterations in the mitochondrial and MB-CK fractions were significantly attenuated after 12 weeks of ACE inhibition. Thus, LV myocardial energy metabolism is progressively impaired and its alteration is not related to the magnitude of geometric changes and LV dysfunction after MI. Most of the beneficial effects of ACE inhibition were observed at 12 weeks after MI. Our results may provide an insight into the therapeutic strategy of ACE inhibition in chronic heart failure after MI.

Products of Angiotensin I Hydrolysis by Human Cardiac Enzymes Potentiate Bradykinin

E. G. Erdös, H. L. Jackman, V. Brovkovych, F. Tan and P. A. Deddish. Products of Angiotensin I Hydrolysis by Human Cardiac Enzymes Potentiate Bradykinin. Journal of Molecular and Cellular Cardiology (2002) 34 , 1569–1576. Some beneficial effects of ACE inhibitors are attributed to potentiation of bradykinin's actions exerted through its B 2 receptor. We investigated them on cultured cells transfected or constitutively expressing both ACE and B 2 receptor. The potentiation of bradykinin was indirect and attributed to a crosstalk induced between enzyme and receptor via ACE, a heterodimer formation. While looking for endogenous activators, we investigated the split products of angiotensin I (Ang) Ang 1–9 and 1–7, peptides released by enzymes of human atria and ventricle. Ang 1–9 was liberated by a cathepsin A-type enzyme, Ang 1–7 by a different metallopeptidase-protease. Cathepsin A's presence in heart tissue was shown by deamidating enkephalinamide substrate, by immunoprecipitation and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. Ang 1–9 and Ang 1–7 potentiated the effect of an ACE-resistant bradykinin analogue on the B 2 receptor in transfected cells expressing human ACE and B 2, and in human endothelial cells. Ang 1–9 and 1–7 augmented arachidonic acid and NO release by bradykinin. NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration by Ang 1–9 and Ang 1–7; at higher concentrations, Ang 1–9 was significantly more active. Both peptides had little activity in absence of bradykinin or ACE. Ang 1–9 and 1–7 potentiated bradykinin action on its B 2 receptor at much lower concentrations than their IC 50 values with ACE. They probably induce conformational changes in the ACE/B 2 receptor complex via interaction with ACE.

Angiotensin-converting enzyme inhibition for the treatment of moderate to severe diabetic retinopathy in normotensive Type 2 diabetic patients: A pilot study

A few reports have suggested that angiotensin-converting enzyme inhibitors (ACE-I) have a beneficial effect on mild diabetic retinopathy (DR). This pilot study was carried out to determine if a small dose of an ACE-I would retard the progression of moderate to severe DR in normotensive Type 2 diabetic patients. Normotensive patients were selected to isolate the effect on the ocular RAS independent of any lowering of blood pressure. Thirty-five normotensive Type 2 diabetic patients with <1+ dipstick proteinuria and with moderate to severe DR by modified Arlie House Classification criteria on seven field stereoscopic photographs through dilated pupils were randomized to an ACE-I (5 mg of enalapril) ( n=18) or to a multivitamin (MVI) placebo ( n=17). They were evaluated by an ophthalmologist every 3 months for a planned duration of 2 years. Endpoints of the study were progression to proliferative DR (PDR) or macular edema (ME) for which laser therapy was necessary or for the development of ≥1+ dipstick proteinuria times two (sustained proteinuria) for which an ACE-I was indicated. There were no differences in baseline age, gender, duration of diabetes, body mass indices, blood pressure, treatment of hyperglycemia or Hb A1C levels between the two groups. Blood pressure and Hb A1C levels did not change in either group during the study. The study was stopped prematurely after a mean duration of 7.2 months after an interim analysis revealed that it was very unlikely that a beneficial effect of ACE-I could be shown. At that time in the ACE-I group, four patients had progressed to PDR, three to ME and one had developed sustained proteinuria. In the MVI group, three patients had progressed to PDR, one to ME and one had developed sustained proteinuria. Small doses of an ACE-I did not exert a beneficial effect on the progression of moderate to severe DR over a short period of follow-up. An analysis of previously published clinical information on the effects of ACE-I, most of which evaluated patients with milder DR, supports only a limited (if any) beneficial effect of this class of drugs on the early stages of this microvascular complication.

Progressive renal and cardiovascular disease: Optimal treatment strategies

Progressive renal and cardiovascular disease: Optimal treatment strategies

Interaction between aspirin and angiotensin-converting enzyme inhibitors: should they be used together in older adults with heart failure?

To determine whether the prostacyclin-inhibiting properties of aspirin counteracts the bradykinin-induced prostacyclin-stimulating effects of angiotensin-converting enzyme (ACE) inhibitors, thereby attenuating the beneficial effects of ACE inhibitors in heart failure patients. Most heart failure patients are older adults. Heart failure is the number one hospital discharge diagnosis of older Americans. The renin-angiotensin system plays a major role in the pathophysiology of heart failure, and ACE inhibitors play a pivotal role in the management of heart failure. Large-scale double-blind randomized trials have demonstrated the survival benefits of using ACE inhibitors in patients with heart failure associated with left ventricular systolic dysfunction. In addition to inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also decrease the breakdown of bradykinin. Bradykinin, a potent vasodilator, acts by stimulating formation of vasodilatory prostaglandins such as prostacyclin, whereas aspirin or acetyl salicylic acid inhibits the enzyme cyclooxygenase, which in turn decreases the production of the prostaglandins. Coronary artery disease and hypertension are the two major underlying causes of heart failure. Most heart failure patients are also on aspirin. There is evidence that aspirin at a daily dose of 80 to 100 mg prevents the synthesis of thromboxane A2 by platelets while relatively sparing the synthesis of prostacyclin in the vascular endothelium. Aspirin at a daily dose of 325 mg has significant inhibitory effects on the vasodilatory prostacyclin synthesis. Studies have demonstrated that, in heart failure patients, low-dose aspirin has no adverse effect on hemodynamic, neurohumoral, or renal functions. Whether the prostacyclin-inhibiting effects of aspirin attenuate some of the beneficial effects of ACE inhibitors mediated by prostacyclin stimulation in heart failure patients is currently unknown. Data from large clinical trials investigating the interaction between aspirin and ACE inhibitors were analyzed to determine the effect of aspirin on the vasodilatory actions of ACE inhibitors in heart failure patients, and the results were analyzed on the basis of theoretical and laboratory findings. The studies included are the Studies of Left Ventricular Dysfunction (SOLVD) (N=6,797), the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) (N=6,090), the Captopril and Thrombolysis Study (CATS) (N=296), and another study involving 317 subjects. The data from these clinical trials investigating the interaction between aspirin and ACE inhibitors included 13,470 subjects. Most of the subjects received aspirin. In the SOLVD study, subjects received aspirin or dipyridamole. Subjects were followed up for an average of about 6 years. In the SOLVD study, subjects were followed up for 41.1 months in the treatment trial and 37.4 months in the prevention trial. Patients who received aspirin or dipyridamole at baseline did not receive the survival benefits of enalapril, whereas patients who received enalapril did not receive the survival benefits of aspirin. In a rather small study of 317 subjects with left ventricular systolic dysfunction (ejection fraction <35%) who were followed up for a relatively longer period of time (5.7 years), the favorable long-term prognosis of patients receiving aspirin was independent of receipt of an ACE inhibitor. A retrospective subgroup analysis of data from the CONSENSUS II study demonstrated that the 6-month mortality rate of patients with acute myocardial infarction (MI) who received enalapril and aspirin was higher than the combined mortality rates of patients receiving enalapril or aspirin alone. This strong interaction between aspirin and the ACE inhibitor enalapril suggests that the survival benefit of enalapril was significantly lower in patients also taking aspirin than in those taking enalapril alone. This interaction was not associated with other nonfatal major events. In the CATS study, use of low-dose aspirin (80 or 100 mg) did not attenuate beneficial effects of captopril (immediate and 1-year follow up) after acute MI. There is a theoretical possibility that the negative interaction between ACE inhibitors and aspirin may reduce the beneficial effects of ACE inhibitors in patients with heart failure, but the information obtained from the existing databases is limited by the retrospective nature of the analyses and does not establish the association definitively. Double-blind randomized controlled trials should be conducted to determine whether such a negative interaction indeed exists.

Modification of Myosin Gene Expression by Imidapril in Failing Heart due to Myocardial Infarction

J. Wang, X. Liu, B. Ren, H. Rupp, N. Takeda and N. S. Dhalla. Modification of Myosin Gene Expression by Imidapril in Failing Heart due to Myocardial Infarction. Journal of Molecular and Cellular Cardiology (2002) 34, 847–857. The beneficial effects of imidapril, an angiotensin converting enzyme (ACE) inhibitor were investigated on changes in myofibrillar ATPase as well as myosin heavy chain (MHC) content and gene expression due to myocardial infarction (MI). Three weeks after occluding the left coronary artery, rats were treated with or without imidapril (1mg/kg/day), for 4 weeks. The infarcted hearts exhibited depressed rates of left ventricular (LV) pressure development (57±2.4% reduction) and pressure decay (55.5±1.6% reduction). LV myofibrillar Ca2+ ATPase activity, unlike that in the right ventricle (RV), was decreased in the infarcted animals compared with controls (6.8±0.4 vs 10.3±0.6μmol Pi/mg/hr). MHC α-isoform contents were decreased by 47 and 41% whereas those of MHC β-isoform were increased by 823 and 1200% in the LV and RV due to MI, respectively. MHC α-isoform mRNA levels were decreased by 55 and 35% whereas those for MHC β-isoform were increased by 50 and 30% in the infarcted LV and RV, respectively. Imidapril treatment partially prevented the changes due to MI in LV function (rate of pressure development, 24±2.3% reduction and rate of pressure decay, 14±1.8% reduction), myofibrillar Ca2+ ATPase activity (8.2±0.7μmol Pi/mg/hr), MHC protein content (α-MHC, 24% reduction and β-MHC, 525% increase) and MHC gene expression (α-MHC, 18% reduction and β-MHC, 15% increase). The results suggest that the beneficial effects of ACE inhibition on the failing heart are associated with improvements in myofibrillar ATPase activities as well as prevention of changes in MHC isozyme protein contents and their gene expression. Copyright 2002 Elsevier Science Ltd. All rights reserved.

Angiotensin-converting enzyme inhibitors improve coronary flow reserve in dilated cardiomyopathy by a bradykinin-mediated, nitric oxide-dependent mechanism.

ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT1 antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM). Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91+/-0.11; enalaprilat, 1.02+/-0.07 mL/min per g; P<0.05) and during atrial pacing (baseline, 0.82+/-0.11; enalaprilat, 0.98+/-0.07; P<0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89+/-0.11; enalaprilat CFR, 2.74+/-0.33; P<0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-L-arginine. The effects were recapitulated by the bradykinin(2) receptor agonist cereport but not by the AT1 antagonist losartan. The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT1 receptor antagonists.

Blockade of endothelial enzymes: new therapeutic targets.

Nitric oxide (NO) is the principal vasoactive substance produced by the vascular endothelium with antitrombotic, antiatherogenic and vasodilator actions. The loss of these functions is now known as endothelial dysfunction (ED) and it has been proposed that it is the final common pathway in cardiovascular disease. At the moment there is an important body of evidence that supports the proposal that ED is a consequence of an imbalance between the free radicals, NO, superoxide (O(-)(2)) and peroxynitrate (ONOO(-)). This imbalance is the result of the actions of well known risk factors associated with an inappropriate diet and infection-inflammation. Angiotensin-converting enzyme (ACE) inhibitors are highly effective against a variety of cardiovascular disorders. Experimental and clinical studies have demonstrated a beneficial effect of ACE inhibition on endothelial function. This action is mainly due to an increase in the concentration of bradykinin, which stimulates NO production. ACE inhibitors also block the formation of angiotensin II that results in a lower production of O(-)(2). These effects lead to improve the imbalance between NO and O(-)(2) observed in cardiovascular disease. This proposal is supported by different clinical trials that have shown that the ACE inhibitors with higher affinity by the tissular ACE, such as quinapril, are the most effective in reversing ED principally by accumulating bradykinin. Recently, the HOPE study conducted in patients at a high risk of cardiovascular events, showed how ramipril, an ACE inhibitor with high affinity by tissular ACE, decreased the mortality rate due to cardiovascular disease independently of changes in blood pressure.

Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure.

The beneficial effects of ACE inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant) are reportedly mediated by NO in heart failure (HF). We hypothesized that in the absence of endothelial NO synthase (eNOS), (1) left ventricular (LV) dysfunction and myocardial remodeling would be more severe after myocardial infarction (MI), and (2) the cardioprotective effect of ACEi and AT(1)-ant would be diminished or absent in mice with HF after MI. eNOS knockout mice (eNOS-/-) and wild-type C57BL/6J (C57) mice (+/+) were subjected to MI by ligating the left coronary artery. One month after MI, each strain was treated with vehicle, ACEi (enalapril, 20 mg/kg per day), or AT(1)-ant (valsartan, 50 mg/kg per day) for 5 months. Echocardiography was performed, and systolic blood pressure was measured before MI and monthly thereafter. Interstitial collagen fraction and myocyte cross-sectional area were examined histologically. We found that (1) compared with C57 mice, eNOS-/- mice that underwent sham surgery had significantly increased systolic blood pressure (P<0.05) and increased LV mass both initially and at 1 to 3 months, although cardiac function and histological findings did not differ between strains; (2) the development of HF and myocardial remodeling were similar after MI in both strains; and (3) ACEi improved cardiac function and remodeling in C57 mice, as evidenced by increased LV ejection fraction (LVEF) and LV shortening fraction (LVSF) and decreased diastolic LV dimension, mass, myocyte cross-sectional area, and interstitial collagen fraction, but these benefits were absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after ACEi, 14.2 +/- 2% versus -4.9 +/- 2.5%, respectively [P<0.001]; increase in LVSF, 8.6 +/- 2.1% versus -7.2 +/- 2.8%, respectively [P<0.01]; and decrease in LV mass, -16.6 +/- 15 versus 73 +/- 23 mm(3), respectively [P<0.01]). AT(1)-ant had benefits similar to those of ACEi, which were also absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after AT(1)-ant, 13.5 +/- 1.8% versus -9.8 +/- 3%, respectively [P<0.001]; increase in LVSF, 6.1 +/- 1.6% versus -3.8 +/- 3.1%, respectively [P<0.01]). Our data suggest that the absence of NO does not alter the development of HF after MI; however, it significantly decreases the cardioprotective effects of ACEi or AT(1)-ant.

Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases

Extracellular matrix accumulation is thought to be involved in the pathogenesis of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting, have not been fully explored. Furthermore, the effect of renoprotective therapies on matrix accumulation through these pathways has not been examined. We investigated the degradative pathway of type IV collagen and the effects of ACE inhibition in experimental diabetic nephropathy. Diabetes was induced in 16 rats by administrating streptozocin; 8 of the diabetic rats were allocated at random to receive the ACE inhibitor perindopril (2 mg/l) in their drinking water and 8 age and weight matched rats served as controls. Gene expression of matrix metalloproteinase ( MMP) and tissue inhibitor of metalloproteinase ( TIMP) was measured by RT-PCR and type IV collagen content by immunohistochemistry. MMP activities were determined by degradation of a radiolabelled substrate and by zymography. Six months of diabetes was associated with a decrease in mRNA and enzymatic activity of MMP-9 (21 % and 51 % respectively, p < 0.05 vs control) and a 51 % increase in TIMP-1 mRNA ( p < 0.05 vs control). By contrast, MMP-2 mRNA was increased but its activity decreased (43 % and 43 % respectively, p < 0.05 vs control). Total degradative capacity of kidney tissue from diabetic rats was also lower (Control: 48 +/- 7 %, Diabetic: 33 +/- 6 %, p < 0.05). Activation of latent MMPs with amino-phenylmercuric acetate increased matrix degradation by two-fold. However the relative decrease associated with experimental diabetes still remained. All diabetes-associated changes in MMP and TIMP mRNA and activities were attenuated by perindopril treatment in association with reduced type IV collagen accumulation. These results indicate that the impairment of matrix degradation contributes to matrix accumulation in diabetic nephropathy and that the beneficial effects of ACE inhibition could in part be mediated by modulation of changes in matrix degradative pathways.

Aspirin impairs reverse myocardial remodeling in patients with heart failure treated with beta-blockers

OBJECTIVESWe hypothesized that aspirin (ASA) might alter the beneficial effect of beta-blockers on left ventricular ejection fraction (LVEF) in patients with chronic heart failure.BACKGROUNDAspirin blunts the vasodilation caused by both angiotensin-converting enzyme (ACE) inhibitors and beta-blockers in hypertensive patients and in patients with heart failure. Several studies suggest that ASA also blunts some of beneficial effects of ACE inhibitors on mortality in patients with heart failure. To our knowledge, there have been no data evaluating the possible interaction of ASA and beta-blockers on left ventricular remodeling in patients with heart failure.METHODSWe retrospectively evaluated patients entered into the Multicenter Oral Carvedilol Heart failure Assessment (MOCHA) trial, a 6-month, double-blind, randomized, placebo-controlled, multicenter, dose-response evaluation of carvedilol in patients with chronic stable symptomatic heart failure. Multivariate analysis was performed to determine if aspirin independently influenced the improvement in LVEF.RESULTSOver all randomized patients (n = 293), LVEF improved 8.2 ± 0.8 ejection fraction (EF) units in ASA nonusers and 4.5 ± 0.7 EF units in ASA users (p = 0.005). In subjects randomized to treatment with carvedilol (n = 231), LVEF improved 9.5 ± 0.9 EF units in ASA nonusers and 5.8 ± 0.8 EF units in ASA users (p = 0.02). In subjects randomized to treatment with placebo (n = 62), LVEF improved 2.8 ± 1.2 EF units in ASA nonusers and 0.5 ± 1.4 EF units in ASA users (p = 0.20). Aspirin did not significantly affect the heart rate or systolic blood pressure response in either the placebo or carvedilol groups. The effect of ASA became more significant on multivariate analysis. The change in LVEF was also influenced by carvedilol dose, etiology of heart failure, baseline heart rate, EF and coumadin use. The detrimental effect of ASA on the improvement in LVEF was dose-related and was present in both placebo and carvedilol groups, although the effect was statistically significant only in the much larger carvedilol group.CONCLUSIONSAspirin significantly affects the changes in LVEF over time in patients with heart failure and systolic dysfunction treated with carvedilol. The specific mechanism(s) underlying this interaction are unknown and further studies are needed to provide additional understanding of the molecular basis of factors influencing reverse remodeling in patients with heart failure.

Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease

Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.

Anti-ischemic effects of angiotensin-converting enzyme inhibitors: a future therapeutic perspective.

The renin-angiotensin system and angiotensin-converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae and the potential of ACE inhibitors to protect the heart is a topic that has emerged recently as a matter for scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function and structure of healthy and damaged hearts and these data support the concept of both primary and secondary cardioprotection with this class of drugs. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, prevention of atherosclerotic lesions and inhibition of myointimal proliferation, extending the concept to a more general definition of cardiovascular protection with ACE inhibitors involving both the heart and the vessels. ACE inhibitors prevent stimulation of smooth muscle cell angiotensin-II (A-II) receptors, thereby blocking both contractile and proliferative actions of A-II. In addition, ACE inhibition of kininase inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favour of those promoting vasodilatory, anti-aggregatory, antithrombotic and antiproliferative effects. Although these data have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction (LVD) and, more recently, also in patients without LVD, cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process and platelets are at least in part responsible. So, the available data underlie the potential benefits of ACE inhibition in the field of ischemic heart disease and atherosclerosis; the results of ongoing studies in humans looking more directly at the influence of ACE inhibitors in this setting are awaited with interest.