Current Pharmaceutical Design, Volume 9, No. 9, 2003
Contents
Applications
of ACE Inhibitors and A2 Receptor Blockers
Executive
Editor: Agostino Molteni
Properties and Distribution of Angiotensin I Converting Enzyme Pp.697-706
Rajko Igic' and Rahim Behnia
Blockade of Apoptosis by ACE Inhibitors and Angiotensin Receptor Antagonists Pp.707-714
Gerasimos Filippatos1 and Brce D. Uhal
The Pulmonary Renin-Angiotensin
System Pp.715-722
Richard
P. Marshall
Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists in Experimental Myocarditis
Pp.723-735
Lisa
M. Godsel, Juan S. Leon and David M. Engman
ACE Inhibitors and AII Receptor Antagonists
in the Treatment and Prevention of Bone Marrow Transplant Nephropathy Pp.737-749
J.E. Moulder, B.L. Fish and E.P. Cohen
Cytostatic Properties of Some Angiotensin
I Converting Enzyme Inhibitors and of Angiotensin II
Type I Receptor Antagonists
Pp.751-761
Agostino Molteni, William F. Ward, Chung H. Ts’ao, JoAnn Taylor, William Small Jr., Loredana Brizio-Molteni and Patricia A. Veno
Angiotensin-Converting Enzyme Inhibitors: Mechanisms of
Action and Implications In Anesthesia Practice Pp.763-776
Rahim Behnia, Agostino Molteni and Rajko Igic
Aprotinin: A Serine Protease Inhibitor with
Therapeutic Actions: Its Interaction with ACE Inhibitors Pp.777-787
Beverly Waxler and Sara F. Rabito
Abstracts
[Back to top] Properties and Distribution of Angiotensin I Converting Enzyme
Rajko Igic and Rahim Behnia
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.
[Back to top] Blockade of Apoptosis by ACE Inhibitors and Angiotensin Receptor Antagonists
Gerasimos Filippatos1 and Bruce D. Uhal
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.
[Back to top] The Pulmonary Renin-Angiotensin
System
Richard
P. Marshall
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.
[Back to top] Angiotensin
Converting Enzyme Inhibitors and Angiotensin II
Receptor Antagonists in Experimental Myocarditis
Lisa
M. Godsel, Juan S. Leon and David M. Engman
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
ÉÉ 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 ÉÉ 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 ÉÉ
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.
[Back to top] ACE Inhibitors and AII Receptor Antagonists in the Treatment and
Prevention of Bone Marrow Transplant Nephropathy
J.E. Moulder, B.L. Fish and E.P. Cohen
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.
[Back to top] Cytostatic Properties of Some Angiotensin
I Converting Enzyme Inhibitors and of Angiotensin II
Type I Receptor Antagonists
Agostino Molteni, William F. Ward, Chung H. Ts’ao,
JoAnn Taylor, William Small Jr., Loredana
Brizio-Molteni and Patricia A. Veno
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.
[Back to top] Angiotensin-Converting Enzyme Inhibitors: Mechanisms of
Action and Implications In Anesthesia Practice
Rahim Behnia, Agostino Molteni and Rajko Igic
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.
[Back to top] Aprotinin: A Serine Protease Inhibitor with
Therapeutic Actions: Its Interaction with ACE
Inhibitors
Beverly Waxler and Sara F. Rabito
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.