Current Pharmaceutical Design - Volume 9, Issue 9, 2003

This review summarizes some basic properties and distribution of angiotensin I converting enzyme (ACE). ACE is one of several biologically important ectoproteins that exists in both membrane-bound and soluble forms. Localized on the surface of various cells, ACE is inserted at the cell membrane via its carboxyl terminus. Human plasma ACE originates from endothelial cells while other body fluids may contain ACE that originates from epithelial, endothelial or germinal cells. The two isoforms of ACE, the two-domain somatic form and the single domain germinal form, convert angiotensin I to angiotensin II, and metabolize kinins and many other biologically active peptides, including substance P, chemotactic peptide and opioid peptides. The broad spectrum of substrates for ACE and its wide distribution throughout the body indicates that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in additional physiologic processes such as neovascularization, fertilization, atherosclerosis, kidney and lung fibrosis, myocardial hypertrophy, inflammation and wound healing. Future research should explore the possible functions of tissue ACE and its systemic role as a pressor agent. ACE inhibitors have achieved widespread use in the treatment of hypertension and the protection of endorgan damage in cardiovascular and renal diseases. Potential problems related to side effects and compliance of such therapy need to be adressed. A safer way of producing therapeutic effects is promised by the delivery of the ACE antisense sequences by a vector producing a permanent inhibition of ACE and long-term control of blood pressure in hypertensive patients.

Inhibitors of angiotensin converting enzyme (ACE-Is) and angiotensin (ANG) receptor antagonists were originally developed to aid in the management of hypertension. As the use of these agents was extended to the management of heart failure and other cardiovascular diseases, studies of tissue remodeling suggested that blockade of ANGII function might play a role in the regulation of cell death by apoptosis. Experiments with cultured cells confirmed that ANGII is an inducer of apoptosis in well differentiated cell types isolated from the heart, kidneys, lungs and other organs. More recent evidence with animal models strongly suggests that ACE-Is and ANG receptor antagonists, in addition to affecting hemodynamics, also influence disease progression through direct inhibition of ANG-induced apoptosis. This manuscript reviews the evidence supporting this view, discusses its potential relevance to disease pathogenesis and offers new hypotheses regarding novel uses of ACE-Is and ANG receptor antagonists in the control of cell death.

The circulating renin-angiotensin system (RAS) has a well-described role in circulatory homeostasis. Recently, local tissue-based RAS have also been described which appear to play a key role in the injury/repair response. The expression of RAS components and the elevation of angiotensin converting enzyme in a number of interstitial lung diseases suggests the existence of a pulmonary RAS and that angiotensin II could mediate, at least in part, the response to lung injury.Activation of a local RAS within the pulmonary circulation and lung parenchyma could influence the pathogenesis of lung injury via a number of mechanisms including an increase in vascular permeability, vascular tone and fibroblast activity, and by reducing alveolar epithelial cell survival. The ability of both ACE inhibitors and angiotensin II receptor antagonists to attenuate experimental lung injury further supports a role for RAS activation and suggests these agents may be useful in the treatment of diffuse parenchymal lung disease. However, further studies are required to delineate the cell types responsible for RAS component expression in the lung and also to identify the key effector molecules of this system. The presence of common polymorphisms in RAS genes and their study in relation to specific physiological phenotypes will aid both our understanding of the role of RAS in the lung and also aid the targeting of future therapies.

Myocarditis is a disease whose pathogenesis is not completely understood and whose prevalence is likely underestimated. Individuals afflicted with this condition may be treated with agents that relieve symptoms arising from inflammation and concurrent cellular damage. One class of drugs commonly used in the treatment of myocarditis includes the angiotensin converting enzyme inhibitors, such as captopril, enalapril and lisinopril, and the angiotensin II receptor antagonists, such as L-158,809 and losartan. The effects of these drugs on cardiomyopathy have been studied using a variety of animal models of heart failure and hypertension. However, less research has been done in the area of animal models of frank myocarditis. Here we review the use of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in animal models of myocarditis. We extend the implications of that published work by correlation with results from studies of other disease models and in vitro experiments that highlight the immunomodulatory potential of these compounds. The literature strongly suggests that aggressive therapy employing angiotensin converting enzyme inhibition and / or blockade of angiotensin II receptors is beneficial. Treatment is useful not only for reducing complications associated with myocarditis, but also for downregulating the potential autoimmune component of disease-without increasing the levels of the infectious agent that may initiate the myocarditis.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway.Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy, an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) type 1 receptor antagonists have strong cytostatic properties on in vitro cultures of many normal and neoplastic cells. They are effective, in particular, in reducing the growth of human lung fibroblasts, renal canine epithelial cells, bovine adrenal endothelial cells, simian T lymphocytes, and of neoplastic cell lines derived from human neuroblastomas, a ductal pancreatic carcinoma of the Syrian hamsters, human salivary glands adenocarcinomas, and two lines of human breast adenocarcinomas.ACE inhibitors are also effective in protecting lungs, kidneys and bladders from the development of nephropathy, pneumopathy, cystitis, and eventually fibrosis in different models of organ-induced damage such as exposure to radiation, chronic hypoxia, administration of the alkaloid monocrotaline or bladder ligation. ACE inhibitors and AII type 1 receptor antagonists are also effective in reducing excessive vascular neoformation in a model of injury to the cornea of rats and rabbits, and in controlling the excessive angiogenesis observed in the Solt-Farber model of experimentally induced hepatoma, in methylcholantrene or radiation-induced fibrosarcomas, in radiation-induced squamous cell carcinomas and in the MA-16 viralinduced mammary carcinoma of the mouse. Captopril was, in addition, effective in controlling tumor growth in a case of Kaposi's sarcoma in humans.The inhibition of AII synthesis and/or its blockade by AII receptors is likely to be an important mechanism for this cytostatic action. The mitogenic effect of AII is well established and a reduction of AII synthesis may well explain cell and neoplasm delayed growth. Moreover, AII regulates and enhances the activity of several growth factors including transforming growth factor B (TGFB) and smooth muscle actin (SMA), and many of these factors are reduced in tissues of animals treated with ACE inhibitors and AII type 1 receptor antagonists. These processes seem to be particularly relevant in the control of fibroblast growth and in the control of the ensuing fibrosis.The ACE inhibitors containing a sulphydril (SH) or thiol radical in their moiety (Captopril and CL242817) seemed to be more effective in controlling fibrosis and the growth of some neoplastic cells than those ACE inhibitors without this thiol radical in their structure, even if the second group of these drugs show in vitro a stronger inhibitory effect on converting enzyme activity. Pharmacologically it is known that ACE inhibitors containing a thiol radical also have antioxidant properties and they are efficient in controlling metalloproteinase action. However, although these additional properties are pharmacologically relevant, the blockade of AII synthesis plays an essential role in the cytostatic activity of these two categories of drugs.These observations underline that in addition to the beneficial effect of these drugs on the cardiovascular system, new potential applications are opening for their wider deployment.

This review summarizes physiology of circulating and local reninangiotensin system (RAS), enzymatic properties and mechanism of action of angiotensin I converting enzyme inhibitors (ACEIs) on RAS, and implications of ACEIs in anesthetic management of patients treated with these drugs. ACEIs, through their effect on RAS, may improve cardiovascular functions, pulmonary dynamics, and body fluid homeostasis. Thus, ACEIs have become an integral part of management of patients with hypertension, congestive heart failure (CHF) and chronic renal disease. ACEIs, due to differences in their chemical structure, exert different pharmacological actions and can have protective or occasional damaging effects on different organs. The anesthesiologists are commonly involved in the management of patients treated with ACEIs. Thus, the role of ACEIs and their possible interaction with anesthetic agents must be an integral part of clinical decision-making during anesthesia Hemodynamic variation during anesthesia is mainly related to specific effects of anesthetic agents on sympathetic nervous system. Those with preoperative fasting, volume depletion and extended sympathetic blockade can have reduced vascular capacitance resulting in decreased venous return, reduced cardiac output and severe arterial hypotension. Angiotensin II (ANG2) a potent vasoconstrictor may counterbalance such hypotensive effect. During ACE inhibition ANG2 cannot counterbalance this hypotension. Thus, induction of anesthesia may cause severe hypotension in hypovolemic patients specifically in those receiving diuretics as a complement to ACEIs. Recent advances in RAS and the pharmacology of ACEIs have identified some predisposing factors and risks associated with anesthesia in patients treated with ACEIs. Practitioners should be vigilant, and readily have vasopressors, necessary fluids and other resuscitative measures for treatment of unexpected hemodynamic instability during anesthesia and surgery.

Aprotinin is an important member of a family of related protease inhibitors and has many clinically beneficial activities. These inhibitors have multiple functions, but not all of them are mediated by enzyme inhibition. Aprotinin has complex effects on many homeostatic functions including coagulation, platelet function and inflammation. It also has complex interactions with other drug therapies including angiotensinconverting enzyme inhibitors. Since patients with cardiovascular diseases are treated frequently with angiotensin-converting enzyme inhibitors and also often need cardiopulmonary bypass surgery and receive aprotinin, these interactions are potentially significant but often overlooked.Aprotinin is currently used to reduce the amount of transfused homologous blood (during cardiopulmonary bypass surgery) and thus, the risks associated with homologous blood transfusion. Aprotinin also has potential uses in acute pancreatitis, carcinoid tumors, sepsis, and other clinical situations. Future research will provide a definitive answer for the need to employ this inhibitor therapeutically in these situations.Aprotinin also has some potentially adverse effects in the kidney in special circumstances. For example, the use of aprotinin in diabetic patients may be related with an increased risk for renal dysfunction. It has also been associated with thrombosis, inadequate coagulation, and allergic reactions. In balance, the available information indicates that the advantages of its application outweigh its disadvantages in most patients.