[Expert Consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease].
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
Roberto Ferrari
Publications and source records attributed to Roberto Ferrari.
Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review.
Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
Cardiotonic Agents↗
Oxidative stress during myocardial ischaemia and heart failure.
Oxidative stress is a condition in which oxidant metabolites exert their toxic effect because of an increased production or an altered cellular mechanism of protection. The heart needs oxygen avidly and, although it has powerful defence mechanisms, it is susceptible to oxidative stress, which occurs, for instance, during post-ischaemic reperfusion. Ischaemia causes alterations in the defence mechanisms against oxygen free radicals, mainly a reduction in the activity of mitochondrial superoxide dismutase and a depauperation of tissue content of reduced glutathione. At the same time, production of oxygen free radicals increases in the mitochondria and leukocytes and toxic oxygen metabolite production is exacerbated by re-admission of oxygen during reperfusion. Oxidative stress, in turn, causes oxidation of thiol groups and lipid peroxidation leading first to reversible damage, and eventually to necrosis. In man, there is evidence of oxidative stress (determined by release of oxidised glutathione in the coronary sinus) during surgical reperfusion of the whole heart, or after thrombolysis, and it is related to transient left ventricular dysfunction or stunning. Data on oxidative stress in the failing heart are scant. It is not clear whether the defence mechanisms of the myocyte are altered or whether the production of oxygen free radicals is increased, or both. Recent data have shown a close link between oxidative stress and apoptosis. Relevant to heart failure is the finding that tumour necrosis factor, which is found increased in failing patients, induces a rapid rise in intracellular reactive oxygen intermediates and apoptosis. This series of events is not confined to the myocytes, but occurs also at the level of endothelium, where tumour necrosis factor causes expression of inducible nitric oxide synthase, production of the reactive radical nitric oxide, oxidative stress and apoptosis. It is therefore, possible that the immunological response to heart failure results in endothelial and myocyte dysfunction through oxidative stress mediated apoptosis. Clarification of these mechanisms may lead to novel therapeutic strategies.
Animals↗
BIRD: Bio-Image Referral Database. Design and implementation of a new web based and patient multimedia data focused system for effective medical diagnosis and therapy.
This paper presents a low cost software platform prototype supporting health care personnel in retrieving patient referral multimedia data. These information are centralized in a server machine and structured by using a flexible eXtensible Markup Language (XML) Bio-Image Referral Database (BIRD). Data are distributed on demand to requesting client in an Intranet network and transformed via eXtensible Stylesheet Language (XSL) to be visualized in an uniform way on market browsers. The core server operation software has been developed in PHP Hypertext Preprocessor scripting language, which is very versatile and useful for crafting a dynamic Web environment.
Database Management Systems↗
Oxidative stress in cardiovascular disease: myth or fact?
Oxidative stress is a mechanism with a central role in the pathogenesis of atherosclerosis, cancer, and other chronic diseases. It also plays a major role in the aging process. Ischemic heart disease is perhaps the human condition in which the role of oxidative stress has been investigated in more detail: reactive oxygen species and consequent expression of oxidative damage have been demonstrated during post-ischemic reperfusion in humans and the protective role of antioxidants has been validated in several experimental studies addressing the pathophysiology of acute ischemia. Although an impressive bulk of experimental studies substantiate the role of oxidative stress in the progression of the damage induced by acute ischemia, not a single pathophysiologic achievement has had a significant impact on the treatment of patients and randomized, controlled clinical trials, both in primary and secondary prevention, have failed to prove the efficacy of antioxidants in the treatment of ischemic cardiovascular disease. This dichotomy, between the experimental data and the lack of impact in the clinical setting, needs to be deeply investigated: certainly, the pathophysiologic grounds of oxidative stress do maintain their validity but the concepts of the determinants of oxidative damage should be critically revised. In this regard, the role of intermediate metabolism during myocardial ischemia together with the cellular redox state might represent a promising interpretative key.
Cardiovascular Diseases↗
Endothelial dysfunction in acute and chronic coronary syndromes: evidence for a pathogenetic role of oxidative stress.
The past two decades have highlighted the pivotal role of the endothelium in preserving vascular homeostasis. Among others, nitric oxide (NO) is currently believed to be the main component responsible for endothelium dependent vasorelaxation and therefore for endothelial function integrity. Reduced NO bioavailability causes the so-called "endothelial dysfunction," which seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions or acute plaque rupture causing unstable angina or myocardial infarction. Compelling evidence is accumulating, stressing the role of oxidative stress in causing reduced NO bioavailability and subsequently endothelial dysfunction (ED). More recently, the role of endothelial cell (EC) apoptosis as a possible final stage of ED and plaque activation has been suggested. In vitro and in vivo evidence suggests a role of oxidative stress also as a putative mechanism finally leading to plaque denudation and activation through increased EC apoptosis. Thus, oxidative stress, irrespective of atherosclerotic disease stages, seems to represent a key phenomenon in vascular disease progression and possible prevention.
Acute Disease↗
TNFalpha in patients with congestive heart failure.
It is now generally accepted that chronically extensive stimulation of the cytokine system-and of TNFalpha in particular-is detrimental to the heart and to peripheral tissue and that such stimulation may contribute to the pathogenesis of congestive heart failure of various causes. During the past decade, basic and clinical research has provided growing evidence for the role of systemic and local inflammatory responses that, however, have so far failed to translate into new treatments for patients. The present paper represents an attempt to critically review the general concepts that lie behind the dichotomy existing between an impressive bulk of biologic research showing the role of TNFalpha as a pathogen in congestive heart failure and the difficulties in translating this evidence into patients' treatment.
Cytokines↗
A composite upstream sequence motif potentiates tRNA gene transcription in yeast.
Transcription of eukaryotic tRNA genes relies on the TFIIIC-dependent recruitment of TFIIIB on a approximately 50 bp region upstream of the transcription start site (TSS). TFIIIC specifically interacts with highly conserved, intragenic promoter elements, while the contacts between TFIIIB and the upstream DNA have long been considered as largely non-specific. Through a computer search procedure designed to detect shared, yet degenerate sequence features, we have identified a conserved sequence pattern upstream of Saccharomyces cerevisiae tDNAs. This pattern consists of four regions in which particular sequences are over-represented. The most downstream of these regions surrounds the TSS, while the other three districts of sequence conservation (appearing as a centrally located TATA-like sequence flanked by T-rich elements on both sides) are located across the DNA region known to interact with TFIIIB. Upstream regions whose sequence conforms to this pattern were found to potentiate tRNA gene transcription, both in vitro and in vivo, by enhancing TFIIIB binding. A conserved pattern of DNA bendability was also revealed, with peaks of bending propensity centered on the TATA-like and the TSS regions. Sequence analysis of other eukaryotic genomes further revealed the widespread occurrence of conserved sequence patterns upstream of tDNAs, with striking lineage-specific differences in the number and sequence of conserved motifs. Our data strongly support the notion that tRNA gene transcription in eukaryotes is modulated by composite TFIIIB binding sites that may confer responsiveness to variation in TFIIIB activity and/or concentration.
Conserved Sequence↗
Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients.
BACKGROUND: The predictive value of heart rate variability (HRV) in chronic heart failure (CHF) has never been tested in a comprehensive multivariate model using short-term laboratory recordings designed to avoid the confounding effects of respiration and behavioral factors. METHODS AND RESULTS: A multivariate survival model for the identification of sudden (presumably arrhythmic) death was developed with data from 202 consecutive patients referred between 1991 and 1995 with moderate to severe CHF (age 52+/-9 years, left ventricular ejection fraction 24+/-7%, New York Heart Association class 2.3+/-0.7; the derivation sample). Time- and frequency-domain HRV parameters obtained from an 8' recording of ECG at baseline and during controlled breathing (12 to 15 breaths/min) were challenged against clinical and functional parameters. This model was then validated in 242 consecutive patients referred between 1996 and 2001 (validation sample). In the derivation sample, sudden death was independently predicted by a model that included low-frequency power (LFP) of HRV during controlled breathing < or =13 ms2 and left ventricular end-diastolic diameter > or =77 mm (relative risk [RR] 3.7, 95% CI 1.5 to 9.3, and RR 2.6, 95% CI 1.0 to 6.3, respectively). The derivation model was also a significant predictor in the validation sample (P=0.04). In the validation sample, LFP < or =11 ms2 during controlled breathing and > or =83 ventricular premature contractions per hour on Holter monitoring were both independent predictors of sudden death (RR 3.0, 95% CI 1.2 to 7.6, and RR 3.7, 95% CI 1.5 to 9.0, respectively). CONCLUSIONS: Reduced short-term LFP during controlled breathing is a powerful predictor of sudden death in patients with CHF that is independent of many other variables. These results refine the identification of patients who may benefit from prophylactic implantation of a cardiac defibrillator.
Death, Sudden, Cardiac↗
Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells: a possible link to pan-coronary syndromes.
BACKGROUND: Endothelial apoptosis of atherosclerotic lesions is a possible determinant for the stable-to-vulnerable plaque transition. Recent data support the notion that plaque activation may be a pan-coronary process, advocating the existence of circulating triggers. METHODS AND RESULTS: Serum from 40 healthy subjects (group 1) and 73 patients with stable angina (n=32; group 2) or acute coronary syndromes (n=41; group 3) was incubated with human umbilical vein endothelial cells. The percentage of apoptosis by flow cytometry and Fas, Bax, and Bcl-2 protein expression by immunoblotting were evaluated at entry in patients and control subjects and repeated after 12 months in group 3. At baseline, apoptotic nuclei were higher in group 3 (14+/-6%) than in group 2 (3.3+/-1.8%) and group 1 (1.35+/-0.8%) (P<0.001). Fas and Bcl-2 were increased in group 3 with respect to groups 1 and 2 (P<0.01). Coincubation of group 3 serum with anti-tumor necrosis factor-alpha and anti-interleukin-6 monoclonal antibodies did not affect the human umbilical vein endothelial cell apoptotic process, whereas addition of Trolox decreased apoptosis to <50%. The percentage of apoptosis in group 3 significantly correlated to the numbers of coronary complex lesions at angiography (r=0.58, P<0.0005). In group 3, apoptosis and the Bax/Bcl-2 ratio decreased at 1 year (P<0.0001, P<0.05 respectively). CONCLUSIONS: Serum from patients with acute coronary syndromes displays a proapoptotic effect on human endothelial cells, supporting the theory of the existence of circulating triggers potentially able to activate atherosclerotic lesions.
Acute Disease↗
Skeletal muscle abnormalities in rats with experimentally induced heart hypertrophy and failure.
BACKGROUND: In congestive heart failure (CHF), function and metabolism of skeletal muscles are abnormal. AIM: To evaluate whether the reduced oxidative capacity of skeletal muscles in CHF is due to impaired O(2) utilisation. METHODS: CHF was induced in rats by injecting 50 mg/Kg monocrotaline. Several animals received the same dose of monocrotaline but only compensated right ventricular hypertrophy and no sign of congestion resulted. Two age- and diet-matched groups of control animals were also studied. In soleus and extensor digitorum longus (EDL) muscles, we studied skeletal muscle blood flow, oxidative capacity and respiratory function of skinned muscle fibres. RESULTS: In CHF, we observed a decrease of muscle blood flow (statistically significant in the soleus, p < 0.05 vs. controls). In compensated rats, a similar trend in blood flow was observed. In both soleus and EDL, a significant reduction of high energy phosphate and a shift of the redox potential towards accumulation of reducing equivalents were observed. The reduction of energy charge was not correlated to the decrease of blood flow. In skinned myofibres, the ratio of O(2) utilised in the presence and in absence of ADP (an index of phoshorilating efficiency) was reduced from 8.9 +/- 1.9 to 2.7 +/- 0.2 (p < 0.001) and from 5.7 +/- 1.0 to 2.0 +/- 0.3 (p < 0.01) in soleus and EDL, respectively. Activity of the different complexes of respiratory chain was investigated by means of specific inhibitors, showing major abnormalities at the level of complex I. In fact, inhibition of VO(2) by rotenone was decreased from 83.5 +/- 3.2 to 36.4 +/- 9.6 % (p < 0.005) and from 81.8 +/- 6.1 to 38.2 +/- 7.4 % (p < 0.005) in soleus and EDL, respectively. CONCLUSIONS: In rats with CHF, abnormalities of oxidative phosphorylation of muscles occur and complex I of the respiratory chain seem to be primarily affected. The metabolic alterations of skeletal muscles in CHF may be explained, at least in part, by an impaired O(2) utilisation.
Animals↗
Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure.
BACKGROUND: In chronic heart failure (CHF), the derangement of autonomic nervous system activity has a deep impact on the progression of the disease. It has been demonstrated that modulation of the renin-angiotensin aldosterone system (RAAS) increases autonomic control of heart rate and reduces adrenergic activity. We sought to evaluate, in CHF, the different effects of an ACE inhibitor (lisinopril) and of an AT1 receptor antagonist (valsartan) on heart rate variability, baroreflex sensitivity and norepinephrine plasma levels. METHODS: Ninety patients (61 +/- 10 years, 2.3 +/- 0.5, New York Heart Association class) with CHF and left ventricular ejection fraction <40% were randomly assigned in a double-blind fashion to receive lisinopril (uptitrated to 20 mg/d) or valsartan (uptitrated to 160 mg/d) therapy for 16 weeks. Heart rate variability (evaluated by measuring standard deviation of normal R-R intervals on 24-hour ECG recordings), spontaneous baroreflex sensitivity and aldosterone and norepinephrine plasma levels were assessed before and after drug therapy. RESULTS: There were no significant differences between valsartan and lisinopril in their effects on left ventricular function, arterial pressure, aldosterone plasma levels and autonomic control of heart rate. Both lisinopril and valsartan significantly reduced plasma norepinephrine levels, but the reduction induced by valsartan was significantly greater than that observed for lisinopril (27% vs 6%, P <.05). CONCLUSIONS: This study shows a comparable effect of ACE inhibition (lisinopril) and of AT1 receptor antagonism (valsartan) on cardiac vagal control of heart rate, whereas valsartan has shown a more effective modulation of sympathetic activity measured by plasma norepinephrine levels.
Angiotensin II Type 1 Receptor Blockers↗
Species-specific modulation of the nitric oxide pathway after acute experimentally induced endotoxemia.
OBJECTIVE: The derangement of the nitric oxide pathway is an important contributing factor to the pathogenesis of septic shock. The aim of this study was to investigate potential differences in modulation of such a pathway in two experimental models of endotoxemia. DESIGN: Prospective, randomized, placebo-controlled animal investigation. SETTING: Cardiovascular research laboratory. SUBJECTS: Male, anesthetized, and mechanically ventilated New-Zealand rabbits (n = 24) and Sprague-Dawley rats (n = 24). INTERVENTIONS: After pretreatment with 1400W (1 mg kg(-1) subcutaneously), an inhibitor of inducible nitric oxide synthase, animals received an intravenous bolus of Escherichia Coli lipopolysaccharides (5 mg kg(-1)). After 4 hrs, lungs, myocardial left ventricles, and aortas were collected. MEASUREMENTS AND MAIN RESULTS: Blood mean arterial pressure, pH, and nitrite/nitrate were monitored. Nitric oxide in the exhaled air was measured by chemiluminescence. Tissue activity of both constitutive nitric oxide synthase and inducible nitric oxide synthase was determined by measuring the conversion of [3H]L-arginine to [3H]L-citrulline. In lipopolysaccharide-treated animals, both mean arterial pressure (after 60 to 90 mins) and blood pH (after 4 hrs) decreased with respect to baseline values. 1400W prevented lipopolysaccharide-induced hypotension only in rats (p <.01). Exhaled nitric oxide decreased in lipopolysaccharide-treated rabbits by 120 mins (from 12.6 +/- 0.6 to 8.4 +/- 0.6 ppb, p <.01) and remained low until the end of the experiment (p <.01 vs. baseline). Conversely, exhaled nitric oxide increased in lipopolysaccharide-treated rats by 120 mins (from 0.4 +/- 0.1 to 5.3 +/- 1.7 ppb, p <.01) and reached a plateau by 210 mins (19.8 +/- 3.1 ppb, p <.01 vs. baseline). 1400W prevented the lipopolysaccharide-induced increase in exhaled nitric oxide and blood nitrite/nitrate in rats (p <.05). Inducible nitric oxide synthase activity increased in endotoxemic rabbit heart (0.19 +/- 0.05 vs. 0.07 +/- 0.02 pmol L-citrulline/min/mg protein in the control group, p <.05) and in all rat tissues, being more striking in the lungs (25.00 +/- 0.01 vs. 0.19 +/- 0.04 pmol L-citrulline/min/mg protein in the control group, p <.001). CONCLUSIONS: The nitric oxide pathway is differently modulated between endotoxemic rabbits and rats.
Amidines↗
Urocortin promotes hemodynamic and bioenergetic recovery and improves cell survival in the isolated rat heart exposed to ischemia/reperfusion.
OBJECTIVES: This study evaluates the hemodynamic, bioenergetic and cytoprotective effects of urocortin (Ucn) in the isolated rat heart exposed to ischemia (I)/reperfusion (R). BACKGROUND: We have previously demonstrated that administration of exogenous Ucn reduces infarct size in ischemic-reperfused rat hearts. METHODS: Urocortin 10(-8)M was added to the perfusate before I, before I and during R, and during R alone in the isolated pulsed rat heart exposed to 35 min I followed by 60 min R. RESULTS: Partial to complete recovery of diastolic pressure and developed pressure was seen irrespective of when Ucn was perfused. In particular, beneficial effects are observed when Ucn is only given during R. Urocortin given only before I, and before I and over R, although not during R alone, also produces significant recovery of high-energy phosphate pools. In each group, improvement in ventricular function is associated with reduction both in myocardial damage, assessed by creatine phosphokinase release, and in endothelial cell and cardiomyocyte apoptosis, assessed by caspase 3 activity and fluorescent-based terminal deoxynucleotidyl transferase mediated nick end labelling enhanced with counterstains. These improvements in ventricular performance, bioenergetics and cell survival are not secondary to any inotropic effects of Ucn. CONCLUSIONS: This is the first report to show enhanced cardiac function induced by Ucn during I/R. Because the cytoprotective and functional benefits are still produced when Ucn is given only at R, these data suggest that Ucn may be useful clinically in the management of myocardial infarction.
Adenosine Triphosphate↗
Cellular thiols redox status: a switch for NF-kappaB activation during myocardial post-ischaemic reperfusion.
Myocardial ischaemia/reperfusion induces NF-kappaB activation, but little is known about the stimuli through which it occurs. Aims of the study were to investigate whether: (a) oxidative stress induced by ischaemia/reperfusion is linked with NF-kappaB activation; (b) counteraction of oxidative stress by N-acetyl cysteine (NAC) reduces NF-kappaB activation. At this purpose, in isolated rat hearts, we induced mild (15 min) and severe (30 min) ischaemia; a group of the hearts submitted to severe ischaemia were treated with NAC. Our data indicate that reperfusion after severe ischaemia activates NF-kappaB: the presence of p65 in the nuclear extracts was 274.5+/-18.6% vs aerobia; (P<0.05) and an induced DNA-binding activity was detected. NF-kappaB translocation occurs in parallel with myocardial decrease in reduced glutathione and protein -SH (from 9.2+/-0.4 to 5.4+/-0.3 nmol/mg prot, P<0.01, and from 350.3+/-16.6 to 296.0+/-9.1 nmol/mg prot, P<0.05) and accumulation of oxidised glutathione-GSSG-(from 0.075+/-0.005 to 0.118+/-0.007 nmol/mg prot, P<0.01). When ischaemia/reperfusion does not result in any oxidative stress (in mild ischaemia or severe ischaemia plus NAC), NF-kappaB does not translocate. A significant correlation was found between the activation of NF-kappaB and the accumulation of GSSG in the myocardium. Our data indicate that an oxidative shift of cellular thiolic pools can modulate the genic transcription of the heart through NF-kappaB activation.
Animals↗
Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS). Rationale and design.
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Adrenergic beta-Antagonists↗
Metabolic approaches to the treatment of ischemic heart disease: the clinicians' perspective.
This review article discusses pharmacological approaches to optimizing myocardial metabolism during ischemia. Fatty acids are the main fuel for the healthy heart, with a lesser contribution coming from the oxidation of glucose and lactate. Myocardial ischaemia dramatically alters fuel metabolism, causing an accelerated rate of glucose conversion to lactate and a switch from lactate uptake by the heart to lactate production. This causes a dramatic disruption in cell homeostasis (e.g. lactate accumulation and a decrease in pH and ATP). Paradoxically, moderately ischemic tissue (approximately 50% of normal flow) continues to derive most of its energy (50-70%) from the oxidation of fatty acids despite a high rate of lactate production. This ischaemia-induced disruption in cardiac metabolism can be minimized by metabolic agents that reduce fatty acid oxidation and increase the combustion of glucose and lactate, resulting in clinical benefit to the ischemic patient. Agents that inhibit fatty acid beta-oxidation, such as ranolazine and trimetazidine, have proven to be effective in the treatment of stable angina. Treatment of acute myocardial infarction patients with an infusion of the glucose-insulin-potassium, which results in suppression of myocardial fatty acid oxidation and greater glucose combustion, has proven effective in reducing mortality. These metabolic therapies are free of direct hemodynamic or chronotropic effects, and thus are well positioned for use alongside traditional agents such as beta-adrenergic receptor antagonists or calcium channel antagonists.
Humans↗
Pathophysiologic and therapeutic importance of tissue ACE: a consensus report.
Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined.
Angiotensin-Converting Enzyme Inhibitors↗