Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 13, 2007
Contents
Part-II
Applications of Angiotensin Converting Enzyme Inhibitors
and of Angiotensin II
Receptor Blockers in Pharmacology and Therapy: An Update
Executive Editor: Agostino Molteni
Editorial: Pp. 1295-1298
Treatment of Experimental Myocarditis via Modulation
of the Renin-Angiotensin System Pp. 1299-1305
M.D. Daniels, K.V. Hyland and D.M. Engman
[Abstract]
Effect of an Angiotensin II Receptor Blocker and Two
Angiotensin Converting Enzyme Inhibitors on Transforming Growth
Factor β
(TGF-β)
and α-Actomyosin
(αSMA),
Important Mediators of Radiation-Induced Pneumopathy and Lung
Fibrosis Pp. 1307-1316
A. Molteni, L.F. Wolfe, W.F. Ward, C.H. Ts’ao, L.B.
Molteni, P. Veno, B.L. Fish, J.M. Taylor, N. Quintanilla,
B. Herndon and J.E. Moulder
[Abstract]
Treatment of Radiation Nephropathy with ACE Inhibitors
and AII Type-1 and Type-2 Receptor Antagonists Pp.
1317-1325
J.E. Moulder, B.L. Fish and E.P. Cohen
[Abstract]
Effects on Cytokines and Histology by Treatment with
the ACE Inhibitor Captopril and the Antioxidant Retinoic Acid
in the monocrotaline Model of Experimentally Induced Lung
Fibrosis Pp. 1327-1333
R.C. Baybutt, B.L. Herndon, J. Umbehr, J. Mein, Y. Xue,
S. Reppert, C. Van Dillen, R. Kamal, A. Halder and A. Molteni
[Abstract]
Role of Renin Angiotensin System Inhibitors in Cardiovascular
and Renal Protection: A Lesson from Clinical Trials
Pp. 1335-1345
L. Stojiljikovic and R. Behnia
[Abstract]
Angiotensin Converting Enzyme Inhibitors in Veterinary
Medicine Pp. 1347-1361
H.P. Lefebvre, S.A. Brown, V. Chetboul, J.N. King, J.L.
Pouchelon
and P.L. Toutain
[Abstract]
General Articles
Transplantation and Other Uses of Human Umbilical
Cord Blood and Stem Cells Pp. 1363-1373
G. Goldstein, A. Toren and A. Nagler
[Abstract]
Retinoids as Differentiating Agents in Oncology: A
Network of Interactions with Intracellular Pathways as the
Basis for Rational Therapeutic Combinations Pp. 1375-1400
E. Garattini, M. Gianni and M. Terao
[Abstract]
Abstracts
[Back to top]
Editorial: Applications of Angiotensin Converting
Enzyme Inhibitors and of Angiotensin II
Receptor Blockers in Pharmacology and Therapy: An Update
About three years ago we discussed in this Journal the development
of additional potential applications of angiotensin converting
enzyme inhibitors and of Angiotensin II (ANG II) receptor
blockers in therapy. The deployment of these drugs in the
treatment of diverse vascular conditions has been, for many
years, a well established medical practice and every year
millions of individuals benefit from this treatment. This
successful deployment underlines the relevance that the renin-angiotensin-aldosterone
system (RAAS) plays in the regulation of the control mechanisms
of our blood pressure and, more in general, of our homeostasis.
It emerged, however, from many articles of that publication
that the RAAS system and ANG II in particular, play additional
roles in the modulation of our homeostasis such as the regulation
of apoptosis, the modulation of cellular growth, specifically
of fibroblasts and endothelial cells, and the modulation of
angiogenesis.
Additional information has been added in the past two-three
years to these data. More knowledge also became available
about the RAAS system genetic regulation, its interaction
with prostaglandins and with other substances also controlling
blood pressure, and about the presence and physiological role
of another converting enzyme: ACE II. The presence of the
various components of the system at local level in several
tissues has also become relevant, especially their action
on the smooth muscle fibers of the wall of arteries and arterioles
of several organs, kidneys, and lungs in particular, or for
the apoptotic regulation of many tissues.
All these observations open the possibility of the deployment
of ACE inhibitors and of A2 receptors antagonists as pharmacological
modulators of many diseases other than hypertension.
This journal’s issue reviews and revises some of the
previous experiences with these drugs and deals with some
novel applications and deployments of them.
Drs. Hamdi and Castellon [1] discuss the role that ACE polymorphism
plays with a large number of diseases including cardiovascular,
metabolic, immune, cancer, aging, neurodegenerative and psychiatric
disorders and they report and summarize these associations.
These observations lead to the question why this ACE polylmorphism
is associated with so many diseases and what its function
is. In the past, much attention has been given to the role
that ACE, especially somatic ACE, plays on the synthesis of
Angiotensin II in different tissues and on the extensive role
that this octapeptide plays in the general homeostasis regulation.
ACE, however, has been found to convert many other peptides
and the investigation of these functions is extended to test
the association of this polymorphism with the levels of other
ACE isoenzymes. The experience with various ACE isoforms and
their effect on cell’s survival may better explain the
ACE/ID polymorphism associated with many diseases.
Drs. Igic and Behnia [2] report the pharmacological, immunological
and genetic targeting of the Renin-Angiotensin system for
the treatment of cardiovascular diseases. The investigators
present the various components of the Renin Angiotensin system
(RAS), discuss the biological activities of angiotensin peptides
and the role of the enzymes that generate and metabolize the
various types of angiotensin. They devote special attention
to the role of Renin, ACE, ACE 2, chymase and neprylysin.
Subsequently, on the basis of the experience with ACE inhibitors
and type 1 ANG II receptor blockers, they discuss the rationale
to target the RAS in its control of general homeostasis. Finally,
they present the investigational agents acting on the RAS,
which posses a potential for clinical deployment and give
the perspective of pharmacological immunological and genetic
targeting of the RAS for the treatment of cardiovascular diseases.
Dr. Heffelfinger [3] discusses the role of RAS in the regulation
of angiogenesis. It is well established that ANGII and bradykinin
are angiogenic agents and affect the microvascular circulation.
That implies that the ACE inhibition would have an impact
on angiogenesis in vivo depending upon which factors
are present in the system. The author reviews several conditions
such as peripheral ischemia, stroke, retinopathy and cancer
in relation to ANGII and bradykinin activity and evaluates
the impact that ACE inhibitors posses in all those clinical
conditions. It appears that peripheral ischemia and stroke
seem to be dependent for angiogenesis regulation by bradykinin
signaling, while cancer and retinopathy are more dependent
upon ANGII. Published data on in vitro cultures as
well in animal models suggest interesting predictions about
how the RAS and bradykinin may function in humans and many
data are now accumulating in humans confirming the data derived
from experimental work. Modulation of angiogenesis by ACE
inhibitors and ANG II receptor blockers may become a new therapeutical
property of these drugs.
Drs. Lazartigues and Lavoie [4] report about the pathophysiology
of the two fACEs present in various tissues, both being components
of the RAS, and about their implications in cardiovascular
diseases. It is now well established that ACE works not only
by generating ANG II but also by interacting with some receptors
outside the RAS like the receptors for bradykinin. More recently
came the discovery of a new ACE homolog identified as ACE2,
which may play a pivotal role in controlling the balance in
the RAS between the vasoconstrictive effect of ANGII and the
vasodilatatory properties of the Angiotensin 1-7 peptide.
ACE2, like ACE, may also hydrolyze peptides not related with
the RAS and this enzyme has also been identified as a receptor
for the severe acute respiratory distress syndrome (SARS)
induced by coronavirus.
In the article, the authors also compare the structure, distribution
and properties of these two carboxypeptidases in the context
of the cardiovascular function since the heart is the organ
where ACE2 activity has been more widely studied. However,
they not only focus their study on the autocrine-paracrine
heart system, but also evaluate ACE2 role on the brain and
indicate potential therapeutic application of the said enzyme
in the treatment of cerebral disorders.
ANGII has been also identified as a proapoptotic and an antifibrotic
factor both in experimental animal models of lung fibrosis
and in humans presenting the ID/DD polymorphism of ACE which
would confer to those individual’s high production of
the enzyme and, consequently, of ANGII. Moreover, lung fibroblasts
isolated from patients suffering with Idiopathic Pulmonary
Fibrosis (IPF) synthetize constitutionally the ANGII precursor
Angiotensinogen (AGT). Uhal and Co. [5] demonstrated that
cultures of lung fibroblasts of patients with IPF synthetize
large amounts of ANGII and ACT in addition to TGFβ1mRNA
and that those effects are limited when the ANGII receptor
antagonist Saralasin is added to the media. Antisense oligonucleotides
against TGFβ1
mRNA or TGFβ1
neutralizing antibodies, when applied to the fibrotic HIPF
cells in serum free media, significantly reduce AGT expression.
In tissue sections from IPF patient biopsies, immunoreactive
AGT/ANGI proteins were detected in myofibroblasts, epithelial
cells and presumptive alveolar macrophages. According to Uhal
et al, [5] all these data support the existence of
an angiotensin TGFβ1
“autocrine loop” in human lung myofibroblasts
and also suggest ANG peptide expression by epithelia and macrophages
in the IPF lung. These findings may explain the ability of
ACE inhibitors and ANG II receptor antagonists to block experimental
lung fibrosis in animals, and support the need for evaluation
of these agents for potential treatment of human IPF.
Apoptosis of alveolar lung epithelial cells (AECs) is also
believed to be critical for the development of Bleomycin (Bleo)-induced
pulmonary fibrosis. Dr. Li and coll. [6] showed that apoptosis
of alveolar epithelial cells in response to Bleo administration
could be abrogated by antisense oligonucleotides against angotensinogen
(AGT) mRNA In a BLEO-induced rat model of pulmonary fibrosis,
endogenous lung AGT was upregulated in vivo as early
as three hours after BLEO instillation as detected by RT-PCR,
in situ hybridization and immunohistochemical staining.
AGT mRNA and angiotensin peptides were localized in type II
alveolar epithelial cells and also localized with alpha-smooth
muscle actin (α-SMA),
a marker of myofibroblasts. Tagged antisense administered
I.T. was specifically accumulated by the lung relative to
liver and kidney, and localized primarily in the epithelium
of airways and cells within alveolar walls. The intratracheal
AGT antisense reduced BLEO-induced pulmonary fibrosis measured
by lung hydroxyproline assay, decreased lung AGT and active
caspase-3 proteins, and reduced the number of apoptotic epithelial
cells but had no effect on the serum ANG II concentration.
These data are consistent with the hypothesis that lung-derived
AGT and local pulmonary ANG II are required for BLEO-induced
pulmonary fibrosis, and suggest the possibility of antisense-based
manipulation of the local angiotensin system as a potential
treatment of fibrotic lung disease.
Recent studies have shown that, in addition to reducing blood
pressure, ACE inhibitors and A2 receptor blockers also modulate
inflammation, adhesion molecule expression, and fibrosis.
To assess the therapeutic potential of these inhibitory agents
for the treatment of inflammatory heart disease, the drugs
have been tested in experimental models of infectious and
autoimmune myocarditis. This review by Drs. Daniels, Hyland,
and Engman [7] summarizes the results of studies examining
the efficacy of angiotensin converting enzyme inhibitors and
angiotensin receptor antagonists for the treatment of mouse
models of virus-induced and parasite-induced myocarditis,
as well as autoimmune cardiomyopathy. The collective results
strongly support the use of renin-angiotensin modulation for
the treatment of myocarditis. Importantly, this therapeutic
approach seems to down regulate autoimmunity without causing
immune suppression which may enhance the survival of the disease-initiating
infectious agent.
There is also a wide range of variability in the efficacy
of various ACE inhibitors and ATR antagonists in models of
experimental myocarditis. These differences might be attributed
to specific pharmacokinetic properties of the individual agents
or the fact that some of agents may have additional activities
other than ACE inhibition or ATR antagonism. The answers to
these questions are not fully clear and further experimentation
is needed to provide a more thorough understanding of the
mechanistic action of these important and widely-used agents.
Progressive, irreversible fibrosis is on of the most clinically
significant consequences of ionizing radiation on normal tissue.
When applied to lungs, it leads to a complication described
as idiopathic pneumonia syndrome (IPS) and eventually to organ
fibrosis. For its high mortality, the condition precludes
treatment with high doses of radiation. There is widespread
interest to understand the pathogenetic mechanisms of IPS
and to find drugs effective in the prevention of its development.
Molteni et al. [8] report their experience with the
protective effects of L 158,809, (an angiotensin II (ANG II)
receptor blocker), and two angiotensin converting (ACE) inhibitors
in the development of IPS and about the role of transforming
growth factor β
(TGF-β)
and of alpha-actomyosin (α
SMA) in the pathogenesis of radiation induced pulmonary fibrosis
in an experimental model of bone marrow transplant (BMT).
When L 158,809, Captopril and Enalapril were added to the
radiation and cytoxan treatment, a significant amelioration
of the histological damage as well as the over expression
of alpha actomyosin were observed. Lung concentrations of
Hydroxproline, PG2, TXA2
and of TGF-β
and alpha actomyosin, two proteins involved in the pathogenesis
of pulmonary fibrosis were restored to normal values. The
finding that ACE inhibitors or ANG II receptor blockers protect
the lungs from radiation induced pneumonitis and fibrosis
reaffirms the role that ANG II plays in this inflammatory
process and suggests an additional indication of treatment
of this condition, thus opening a new potential pharmacologic
use of these drugs.
This experiment in vivo also confirms the in
vitro data of Uhal and coll. on the role of TGFβ1
and SM actomyosin in the regulation of fibroblasts and macrophages
growth and the antagonistic effect of ACE inhibitors and ANGII
receptor blockers on such growth.
ANG II also plays a role in the development of renal fibrosis.
This is particularly apparent in models of radiation-induced
nephropathy and it is like for the lungs, a severe limiting
factor in the treatment of radiotherapy for patients. Development
of renal fibrosis has emerged as a significant complication
of bone marrow transplantation and of radionuclide therapy.
The ameliorative action of different ACE inhibitors, Captopril,
in particular and of ANGII type 1 and type 2 receptor antagonists
in the treatment of renal fibrosis is well established.
Moulder, and coll. [9] discuss in their article the difference
between mitigation and treatment of radiation-induced nephropathy
which implies that different mechanisms are operating in the
pathogenesis of this process.
First, a high-salt diet is effective in the mitigation of
radiation nephropathy, but deleterious on the treatment of
established disease. Second, AT1
blockage and ACE inhibition is highly dependent on drug dose
in mitigation of radiation nephropathy, but not so in treatment.
Finally, while AT1 blockage
is effective in mitigation of radiation nephropathy, it does
not do so in treatment. The authors hypothesize that while
mitigation of radiation nephropathy works by suppression of
the RAS, treatment of established radiation nephropathy requires
blood pressure control in addition to (or possibly instead
of) RAS suppression.
Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from
the shrub Crotalaria spectabilis induces in the lungs
of many mammalian species severe hypertension and fibrosis.
Previous work with MCT-induced lung disease in rats has shown
that some of the steps to progressive fibrosis can be interrupted
or decreased by intervention with retinoic acid (RA) or with
the angiotensin converting enzyme inhibitor, captopril. The
report by Baybutt et al. [10] emphasizes the pathology
and cytokines present in lungs of rats in the MCT model of
hypertension and fibrosis in animals treated with captopril,
retinoic acid or a combination of both drugs. TGFβ
was depressed at 30 days by MCT, an effect reversed by a combination
of captopril and RA. RA influences production of an important
Th1 cytokine, IFNγ,
and demonstrated the greatest limitation of MCT-induced TNFα.
The MCT-induced lung pathology of vasculitis, interstitial
pneumonia and fibrosis was limited by captopril. Smooth muscle
actin was overexpressed in MCT treated animals receiving RA,
an effect also observed with treatment with both captopril
and RA. No synergistic or antagonistic activity was observed
when the two drugs were administered together. Each of the
drugs exerts different and particular effects on serum and
tissue levels of various cytokines, suggesting that each drug
is efficient at different points of attack in control of lung
fibrosis.
In the past few years many clinical trials testing the efficacy
of ACE inhibitors (ACEI) and of ANG II receptor blockers have
been conducted. Most of these trials were run in patients
suffering either cardiovascular diseases or renal diseases.
An extensive review of these clinical trials is presented
in this issue by Stojiljkovic and Behnia [11].
In patients with heart failure (HF), ACEI have been shown
to reduce overall mortality and mortality from cardiovascular
causes, to increase life expectancy, as well as to preserve
the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS
trials). In addition, in PROGRESS study ACEI substantially
decreased the risk of stroke and transient ischemic attacks
in patients with cerebrovascular disorders. The HOPE and EUROPA
studies confirmed that long term therapy with ACEI provides
significant survival benefit in patients with a broad range
of atherosclerotic cardiovascular diseases. After these large
and well designed clinical studies, ACEI have become standard
therapy for routine secondary prevention in all patients with
cardiovascular diseases, unless contraindicated.
AT1 receptor blockers have been more recently added to the
cardiovascular therapeutic armamentarium. They are believed
to provide additional protection by inhibition of locally
synthesized angiotensin II on the level of AT1 receptor. ELITE
II, ValHeFT and CHARM studies have shown that AT1 receptor
blockers are equally effective as ACEI in reduction of mortality
and morbidity in patients with HF. Importantly, they may be
used together with ACEI, or as alternative treatment in ACEI
intolerant patients.
Renal protection is another important effect of both ACE and
AT1 receptor blockers that has been confirmed in several large
clinical trials. North American Microalbuminemia Study group
and EUCLID group demonstrated significant reduction in progression
of diabetic nephropathy in patients with insulin dependent
diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers
are mainly studied in the non-insulin dependent diabetes mellitus
(NIDDM) nephropathy. Four recent clinical trials (IRMA-2,
DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor
blockers in patients with NIDDM nephropathy. These studies
confirmed the beneficial effect of AT1 receptor blockers in
patients with NIDDM nephropathy that was extended beyond the
blood pressure reduction. Ongoing studies (ONTARGET, TRANSCENT
and PROTECTION) should provide us with additional insights
about cardiovascular, renal and other end-organ protective
effects of these therapeutic agents.
Clinical trials were also conducted in veterinary medicine,
especially for the treatment of small animals (canines and
felines). Dr. Lefevre and coll. [12] present and discuss the
veterinary experience with ACE inhibitors. Less information
from trials with ANGII receptor blockers are presently available.
ACE inhibitors currently approved for use in veterinary medicine
are benazepril, enalapril, imidapril and ramipril. They are
all pro-drugs administered by oral route. ACE inhibitors are
generally well tolerated.
Benazepril, enalapril, imidapril and ramipril are approved
for treatment of dogs with chronic heart failure (CHF). The
efficacy of ACE inhibitors has been convincingly demonstrated
in dogs with CHF, especially in those with chronic valvular
disease. In such clinical settings, ACE inhibitors improve
hemodynamics and clinical signs, and increase survival time.
In cats with cardiovascular disease, little information is
available except for reports of some benefit in cats with
hypertrophic cardiomyopathy in two non-controlled investigations.
ACE inhibitors have also a mild or moderate hypotensive effect.
There is also evidence to recommend ACE inhibitors in dogs
and cats with chronic renal failure (CRF). They decrease the
glomerular capillary pressure, have antiproteinuric effects,
tend to delay the progression of CRF and to limit the extent
of renal lesions.
It is presumptuous to suggest that all the new potential developments
and the new therapeutic applications of ACE inhibitors and
ANG II receptor antagonists have been discussed in this journal
issue. The wide variety of applications and the successful
results seen with the deployment of these drugs in the prevention
of fibrotic processes which ensue in many organs as end-point
damage of various injuries and the potential cytostatic properties
observed both on a variety of cultures of cell lines or in
different types of experimentally induced malignancies open
new ways to use these drugs. If the clinical trials which
are currently on course confirm the successful results observed
at the experimental level, a significant improvement will
derive for the treatment of diseases for which present therapies
are currently limited.
Acknowledgements
The editor wishes to thank Ms’s Kathy Rode and Marilyn
Hall for their invaluable help in dealing with the correspondence
with the authors of the various articles and with Bentham
Co., the publisher, in Karachi, Pakistan.
References
[1] Castellon R, Hamdi HK. Demystifying the ACE Polymorphism:
From Genetics to Biology. Curr Pharm Des 2007; 13(12): 1191-1198.
[2] Igic R, Behnia R. Pharmacological, Immunological, and
Gene Targeting of the Renin-Angiotensin System for Treatment
of Cardiovascular Disease. Curr Pharm Des 2007; 13(12): 1199-1214.
[3] Heffelfinger SC. The Renin Angiotensin System in the Regulation
of Angiogenesis. Curr Pharm Des 2007; 13(12): 1215-1229.
[4] Lazartigues E, Lavoie JL. The two fACEs of the Tissue
Renin-Angiotensin Systems: Implications in Cardiovascular
Diseases. Curr Pharm Des 2007; 13(12): 1231-1245.
[5] Uhal BD, Kim YK, Li XP, Molina-Molina M. Angiotensin-TGF-β1
Crosstalk in Human Idiopathic Pulmonary Fibrosis: Autocrine
Mechansism in Myofibroblasts and Macrophages. Curr Pharm Des
2007; 13(12): 1247-1256.
[6] Li X, Zhuang J, Rayford H, Zhang H, Shu R, Uhal B. Attenuation
of Bleomycin-Induced Pulmonary Fibrosis by Intratracheal Administration
of antisense Oligonucleotides against angiotensinogen mRNA.
Curr Pharm Des 2007; 13(12): 1257-1268.
[7] Daniels MD, Hyland KV, Engman DM.Treatment of Experimental
Myocarditis via Modulation of the Renin-Angiotensin System.
Curr Pharm Des 2007; 13(13): 1299-1305.
[8] Molteni A, Wolfe LF, Ward WF, Ts’ao CH, Molteni
LB, Veno P, Fish BL., Taylor JM, Quintanilla N, Moulder JE.
Effect of an Angiotensin II Receptor Blocker and Two Angiotensin
Converting Enzyme Inhibitors on Transforming Growth Factor
β (TGF-β)
and α-Actomyosin
(αSMA),
Important Mediators of Radiation-Induced Pneumopathy and Lung
Fibrosis. Curr Pharm Des 2007; 13(13): 1307-1316.
[9] Moulder JE, Fish BL, Cohen EP. Treatment of Radiation
Nephropathy with ACE Inhibitors and AII Type-1 and Type-2
Receptor Antagonists. Curr Pharm Des 2007; 13(13): 1317-1325.
[10] Baybutt RC, Herndon BL, Umbehr J, Main J, Xue Y, Van
Dillen C, Halder A, Molteni A. Effects on Cytokines and Histology
by Treatment with the ACE Inhibitor Captopril and the Antioxidant
Retinoic Acid in the monocrotaline Model of Experimentally
Induced Lung Fibrosis. Curr Pharm Des 2007; 13(13): 1327-1333.
[11] Stojiljikovic L, Behnia R. Role of Renin Angiotensin
System Inhibitors in Cardiovascular and Renal Protection:
A Lesson from Clinical Trials. Curr Pharm Des 2007; 13(13):
1335-1345.
[12] Lefebvre HP, Brown AA, Chetboul V, King JN, Pouchelon
JL, Toutain PL. Angiotensin Converting Enzyme Inhibitors in
Veterinary Medicine. Curr Pharm Des 2007; 13(13): 1347-1361.
Agostino Molteni
Departments of Pathology and Pharmacology
University of Missouri- Kansas City
School of Medicine, Kansas City
Missouri 64108, USA
Tel: 816-235-5604
Fax: 816-235-5172
E-mail: moltenia@umkc.edu
[Back to top]
Treatment of Experimental Myocarditis via Modulation
of the Renin-Angiotensin System
M.D. Daniels, K.V. Hyland and D.M. Engman
The renin-angiotensin system is primarily responsible for
regulating vascular tone. Drugs that inhibit this pathway,
angiotensin-converting enzyme inhibitors and angiotensin receptor
antagonists, are widely used to treat hypertension and a variety
of cardiomyopathies. Recent studies have shown that, in addition
to reducing blood pressure, these drugs also modulate inflammation,
adhesion molecule expression, and fibrosis. To assess the
therapeutic potential of these inhibitory agents for the treatment
of inflammatory heart disease, the drugs have been tested
in experimental models of infectious and autoimmune myocarditis.
This review summarizes the results of studies examining the
efficacy of angiotensin converting enzyme inhibitors and angiotensin
receptor antagonists for the treatment of mouse models of
virus-induced and parasite-induced myocarditis, as well as
autoimmune cardiomyopathy. The collective results strongly
support the use of renin-angiotensin modulation for the treatment
of myocarditis. Importantly, this therapeutic approach seems
to downregulate autoimmunity without causing immune suppression
which may enhance the survival of the disease-initiating infectious
agent.
[Back to top]
Effect of an Angiotensin II Receptor Blocker and Two
Angiotensin Converting Enzyme Inhibitors on Transforming Growth
Factor β
(TGF-β)
and α-Actomyosin
(αSMA),
Important Mediators of Radiation-Induced Pneumopathy and Lung
Fibrosis
A. Molteni, L.F. Wolfe, W.F. Ward, C.H. Ts’ao, L.B.
Molteni, P. Veno, B.L. Fish, J.M. Taylor, N. Quintanilla,
B. Herndon and J.E. Moulder
Progressive, irreversible fibrosis is one of the most clinically
significant consequences of ionizing radiation on normal tissue.
When applied to lungs, it leads to a complication described
as idiopathic pneumonia syndrome (IPS) and eventually to organ
fibrosis. For its high mortality, the condition precludes
treatment with high doses of radiation. There is widespread
interest to understand the pathogenetic mechanisms of IPS
and to find drugs effective in the prevention of its development.
This report summarizes our experience with the protective
effects of L 158,809, an angiotensin II (ANG II) receptor
blocker, and two angiotensin converting enzyme (ACE) inhibitors
in the development of IPS and the role of transforming growth
factor β
(TGF-β)
and of alpha-actomyosin (α
SMA) in pathogenesis of radiation induced pulmonary fibrosis
in an experimental model of bone marrow transplant (BMT).
Male WAG/Riji/MCV rats received total body irradiation and
a regimen of cyclophosphamide (CTX) in preparation for bone
marrow transplant. While one group of animals remained untreated,
the remainders were subdivided into three groups, each of
them receiving either the ANG II receptor blocker or one of
the two ACE inhibitors (Captopril or Enala-pril). Each of
the three drugs was administered orally from 11 days before
the transplant up to 56 days post transplant. At sacrifice
time the irradiated rats receiving only CTX showed a chronic
pneumonitis with septal fibrosis and vasculitis affecting,
in particular, small caliber pulmonary arteries and arterioles.
Their lung content of hydroxyproline was also markedly elevated
in association with the lung concentrations of thromboxane
(TXA2) and prostaglandin (PGI2),
(two markers of pulmonary endothelial damage). A significant
increase of alpha actomyosin staining was observed in vessels,
septa and macrophages of the same animals which also overexpressed
TGF-β.
When L 158,809, Captopril and Enalapril were added to the
radiation and cytoxan treatment, a significant amelioration
of the histological damage as well as the overexpression of
α SMA
was observed. Lung concentrations of hydroxyproline, PGI2,
TXA2 and TGF-β
were also observed in these animals so that the values of
these compounds were closer to those measured in untreated
control rats than to their irradiated and cytoxan treated
counterparts. Angiotensin II plays an important role in the
regulation of TGF-β
and α
SMA, two proteins involved in the pathogenesis of pulmonary
fibrosis. The finding that ACE inhibitors or ANG II receptor
blockers protect the lungs from radiation induced pneumonitis
and fibrosis reaffirms the role that ANG II plays in this
inflammatory process and suggests an additional indication
of treatment of this condition, thus opening a new potential
pharmacologic use of these drugs.
[Back to top]
Treatment of Radiation Nephropathy with ACE Inhibitors
and AII Type-1 and Type-2 Receptor Antagonists
J.E. Moulder, B.L. Fish and E.P. Cohen
Radiation nephropathy has emerged as a significant complication
of bone marrow transplantation and radionuclide radiotherapy,
and is a potential sequela of radiological terrorism and radiation
accidents. In the early 1990's, it was demonstrated that experimental
radiation nephropathy could be treated with a thiol-containing
ACE inhibitor, captopril. Further studies have shown that
enalapril (a non-thiol ACE inhibitor) is also effective in
the treatment of experimental radiation nephropathy, as are
both AII type-1 (AT1) and
type-2 (AT2) receptor antagonists.
ACE inhibitors and AII receptor antagonists are also effective
in the mitigation (prevention) of radiation nephropathy. Other
types of antihypertensive drugs are ineffective in mitigation,
but brief use of a high-salt diet in the immediate post-irradiation
period significantly decreases renal injury.
There are differences between mitigation and treatment of
radiation nephropathy that imply that different mechanisms
are operating. First, a high-salt diet is effective in the
mitigation of radiation nephropathy, but deleterious on the
treatment of established disease. Second, AT1
blockade is more effective than ACE inhibition for mitigation
of radiation nephropathy, but equally effective for treatment.
Third, the efficacy of AT1
blockade and ACE inhibition is highly dependent on drug dose
in mitigation of radiation nephropathy, but not so in treatment.
Finally, while AT2 blockade
augments the benefit of AT1
blockade in mitigation of radiation nephropathy, it does not
do so in treatment. We hypothesize that while mitigation of
radiation nephropathy works by suppression of the renin-angiotensin
system, treatment of established radiation nephropathy requires
blood pressure control in addition to (or possibly instead
of) suppression of the renin-angiotensin system.
[Back to top]
Effects on Cytokines and Histology by Treatment with
the ACE Inhibitor Captopril and the Antioxidant Retinoic Acid
in the monocrotaline Model of Experimentally Induced Lung
Fibrosis
R.C. Baybutt, B.L. Herndon, J. Umbehr, J. Mein, Y. Xue,
S. Reppert, C. Van Dillen, R. Kamal, A. Halder and A. Molteni
Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from
the shrub Crotalaria spectabilis, induces in the
lungs of many mammalian species severe hypertension and fibrosis.
Previous work with MCT-induced lung disease in rats has shown
that some of the steps to progressive fibrosis can be interrupted
or decreased by intervention with retinoic acid (RA) or with
the angiotensin converting enzyme inhibitor, captopril. This
report emphasizes the pathology and cytokines present in lungs
of rats in the MCT model of hypertension and fibrosis in 8
treatment groups, six per group: (1) controls, not treated;
(2) captopril; (3) RA; (4) combined captopril and RA. Groups
5-8 replicated groups 1-4 and also received MCT subcutaneously.
Tissues were harvested at 28 days for histopathology and measurement
of cytokines TGFβ,
TNFα
interleukin 6, and IFNγ.
TGFβ
was depressed at 28 days by MCT, an effect reversed by a combination
of captopril and RA. RA influences production of an important
Th1 cytokine, IFNγ,
and demonstrated the greatest limitation of MCT-induced TNFα.
The MCT-induced lung pathology of vasculitis, interstitial
pneumonia and fibrosis was limited by captopril. Smooth muscle
actin was overexpressed in MCT treated animals receiving RA,
an effect reduced with captopril. Overall, the study confirmed
the existence of a protective effect for both captopril and
RA from MCT-induced lung damage at 30 days. No synergistic
or antagonistic activity was observed when the two drugs were
administered together. Each of the drugs exerts different
and particular effects on serum and tissue levels of various
cytokines, suggesting that each drug is efficient at different
points of attack in the control of lung fibrosis.
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Role of Renin Angiotensin System Inhibitors in Cardiovascular
and Renal Protection: A Lesson from Clinical Trials
L. Stojiljikovic and R. Behnia
Beneficial effects of angiotensin converting enzyme inhibitors
(ACEI) and angiotensin type 1 receptor (AT1) blockers in patients
with cardiovascular and renal diseases have been clearly demonstrated
in numerous large outcomes studies. In patients with heart
failure (HF), ACEI have been shown to reduce overall mortality,
mortality from cardiovascular causes, to increase life expectancy,
as well as to preserve the renal function (CONSENSUS, SAVE,
TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS
study ACEI substantially decreased the risk of stroke and
transient ischemic attacks in patients with cerebrovascular
disorders. The HOPE and EUROPA studies confirmed that long
term therapy with ACEI provides significant survival benefit
in patients with broad range of atherosclerotic cardiovascular
diseases. After these large and well designed clinical studies,
ACEI have become standard therapy for routine secondary prevention
in all patients with cardiovascular diseases, unless contraindicated.
AT1 receptor blockers have been recently added to the cardiovascular
therapeutic armamentarium. They are believed to provide additional
protection by inhibition of locally synthesized angiotensin
II on the level of AT1 receptor. The ELITE II, ValHeFT and
CHARM studies have shown that AT1 receptor blockers are equally
effective as ACEI in reduction of mortality and morbidity
in patients with HF. Importantly, they may be used together
with ACEI, or as alternative treatment in ACEI intolerant
patients.
Renal protection is another important effect of both ACEI
and AT1 blockers that has been confirmed in several large
clinical trials. The North American Microalbuminemia Study
group and EUCLID group demonstrated significant reduction
in progression of diabetic nephropathy in patients with insulin
dependent diabetes mellitus (IDDM) treated with ACEI. AT1
receptor blockers are mainly studied in the non-insulin dependent
diabetes mellitus (NIDDM) nephropathy. Four recent clinical
trials (IRMA-2, DETAIL, RENAAL and IDNT) examined the effect
of AT1 receptor blockers in patients with NIDDM nephropathy.
These studies confirmed the beneficial effect of AT1 receptor
blockers in patients with NIDDM nephropathy that was extended
beyond the blood pressure reduction. Ongoing studies (ONTARGET,
TRANSCEND and PROTECTION) should provide us with additional
insights about cardiovascular, renal and other end-organ protective
effects of these therapeutics.
[Back to top]
Angiotensin Converting Enzyme Inhibitors in Veterinary
Medicine
H.P. Lefebvre, S.A. Brown, V. Chetboul, J.N. King, J.L.
Pouchelon
and P.L. Toutain
Angiotensin-converting enzyme (ACE) inhibitors represent one
of the most commonly used categories of drugs in canine and
feline medicine. ACE inhibitors currently approved for use
in veterinary medicine are benazepril, enalapril, imidapril
and ramipril. They are all pro-drugs administered by oral
route. A physiologically based model taking into account the
saturable binding to ACE has been developed for pharmacokinetic
analysis. The bioavailability of the active compounds from
their respective pro-drug is low. The active metabolites are
eliminated by renal, hepatorenal or biliary excretion, according
to the drug. The elimination half-life of the free fraction
of the active compounds is very short (ranging from approximately
10 min to 2 h). ACE inhibitors are generally well tolerated.
Benazepril, enalapril, imidapril and ramipril are approved
for dogs with chronic heart failure (CHF). The efficacy of
ACE inhibitors has been convincingly demonstrated in dogs
with CHF, especially in those with chronic valvular disease.
In such clinical settings, ACE inhibitors improve hemodynamics
and clinical signs, and increase survival time. In cats with
cardiovascular disease, little information is available except
for reports of some benefit in cats with hypertrophic cardio-myopathy
in two non-controlled investigations. ACE inhibitors have
also a mild to moderate hypotensive effect.
There is also evidence to recommend ACE inhibitors in dogs
and cats with chronic renal failure (CRF). They decrease the
glomerular capillary pressure, have antiproteinuric effects,
tend to delay the progression of CRF and to limit the extent
of renal lesions.
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Transplantation and Other Uses of Human Umbilical
Cord Blood and Stem Cells
G. Goldstein, A. Toren and A. Nagler
Human umbilical cord blood (CB) has established itself as
a legitimate source for hematopoeitic stem cell transplantations.
Since the first transplantation was preformed in 1988, it
is estimated that approximately 4,000 patients, with malignant
and non-malignant diseases, were transplanted with CB. Comparing
to bone marrow transplants, cord blood's collection is easier
and safer. It is also quicker to perform CB transplantation
from the time of beginning of donor search. One of the major
advantages of it is the naïve nature of newborn's immune
system. This allows transplantations with less restriction
of the HLA system, and with fewer graft versus host disease
(GVHD) cases. A true setback of CB transplantations is the
slow pace of engraftment. This fact has negative impact on
treatment related mortality and is related to the amount of
stem cell infused. Since CB has limited nucleated cell dose,
transplanting it to heavier patients, namely adults, pauses
many difficulties. But the skepticism about the possibility
that CB might be used in adult hematopoetic stem cell transplantations,
can decline after few large scale trials have shown that it
is definitely a feasible procedure. Few fields of research
might help to improve the outcome of CB transplantations.
While some strategies are at different investigational stages,
others are at advanced phases of clinical studies. Main strategies
are based on expansion of the number of the stem cells in
CB grafts, induction of a temporary engraftment with other
stem cell sources, or reduction of the toxicity of the conditioning
regimens.
It is encouraging to witness that the outcome of CB transplantations
is improving constantly. Other potential uses of CB are also
discussed. It was used for gene transfer for primary immune
deficiency, and it was also demonstrated in animal models
that its stem cell could serve as regenerative cells in non-hematopoeitic
injured tissues.
CB has broad spectrum of possible uses, but hematopoeitic
stem cell transplantation is still the major indication. In
an era where 30-40% of patients will not have a matched related
or unrelated donor, CB is a major alternative, which provide
a true chance for cure for a wide variety of diseases.
[Back to top]
Retinoids as Differentiating Agents in Oncology: A
Network of Interactions with Intracellular Pathways as the
Basis for Rational Therapeutic Combinations
E. Garattini, M. Gianni and M. Terao
Retinoic acid and natural as well as synthetic derivatives
(retinoids) are promising anti-neoplastic agents endowed with
both therapeutic and chemopreventive potential. Although the
treatment of acute promyelocic leukemia with all-trans retinoic
acid is an outstanding example, the full potential of retinoids
in oncology has not yet been exploited and a more generalized
use of these compounds is not yet a reality. This may be the
result of issues such as natural and induced resistance as
well as local and systemic toxicity. One way to enhance the
therapeutic and chemopreventive activity of retinoic acid
and derivatives is to identify rational combinations between
these compounds and other pharmacological agents. This is
now possible given the wealth of information available on
the biochemical and molecular mechanisms underlying the biological
activity of retinoids. At the cellular level, the anti-leukemia
and anti-cancer activity of retinoids is the result of three
main actions, cell-differentiation, growth inhibition and
apoptosis. At the molecular level, retinoids act through the
activation of nuclear-retinoic-acid-receptor-dependent and-independent
pathways. The cellular pathways and molecular networks relevant
for retinoid activity are modulated by a panoply of other
intra-cellular and extra-cellular pathways that may be targeted
by known drugs and other experimental therapeutics. The review
article aims to summarize and critically discuss the available
knowledge in the field and provide a rational framework that
may be useful for the design of effective drug combinations
with the potential to enhance the therapeutic index of retinoids.
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