Can
pharmacologic treatment initiated shortly before reperfusion salvage
ischemic myocardium?
Michael V. Cohen1,2 , James
M. Downey1
1 Department of Physiology, University of South
Alabama, College of Medicine,
Mobile, AL, USA
2 Department of Medicine, University of South
Alabama, College of Medicine,
Mobile, AL, USA
Correspondence: Dr Michel V. Cohen, Department of Physiology,
MSB 3050, University of South Alabama, College of Medicine, Mobile,
AL 36688, USA. Tel: +1 334 460 6812, e-mail:
mcohen@usamail.usouthal.edu
Coronary artery disease is still the leading cause
of death in the United States. Because it is now well accepted
that the formation of an intracoronary thrombus is the final step
in the pathogenesis of coronary occlusion, early reperfusion therapy
is acknowledged to be a very effective means of salvaging ischemic
myocardium. The introduction of thrombolytic agents for the treatment
of acute myocardial infarction has strikingly altered the approach
to acute coronary thrombosis and has reduced mortality. The current
recommendation is reperfusion within a period not exceeding 6
h after onset of chest pain. Reperfusion may be effected either
pharmacologically with a thrombolytic agent or mechanically with
angioplasty or bypass surgery.
However, it must be realized that despite the on-call availability
of interventional catheterization teams in major clinical centers,
there is an unavoidable delay until the coronary artery can be
opened; and if thrombolysis is chosen, this process still may
take 1–2 h. When myocardium is deprived of arterial blood delivering
oxygen, reperfusion delays translate into necrosis. Thus, while
reperfusion therapy has reduced the amount of infarction, the
latter has not been eliminated. Therefore, there has been an intense
effort to develop strategies that will preserve viability of ischemic
tissue in the period before reperfusion can be established.
There is also evidence that the very process which rescues ischemic
myocardium, ie, reperfusion, may also be the cause of additional
damage to the tissue, the so-called reperfusion injury. When ischemic
myocardium is reperfused, its appearance rapidly changes from
that of normal tissue to one characterized by obvious necrosis.
It is unclear whether this reflects additional necrosis resulting
from reperfusion or whether it is simply the expression of irreversible
damage incurred during ischemia. Many causes of this reperfusion
injury have been suggested: oxygen free radicals, increases in
intracellular Ca++ content, neutrophil recruitment, complement
activation, disturbed endothelial function leading to the no-reflow
phenomenon, impaired cellular energetics, and damage to the extracellular
collagen matrix. Unfortunately, reperfusion injury has been difficult
to prove, and establishment of a mechanism has been elusive.
There are a number of established interventions which utilize
the mechanism of ischemic preconditioning to salvage ischemic
myocardium.[1] Unfortunately, the majority of
clinically acceptable agents require pretreatment to be effective.
Obviously the need for pretreatment limits this form of protection
to patients undergoing revascularization surgery or possibly angioplasty,
but would not be suitable for patients admitted with acute myocardial
infarction.
Sodium-hydrogen exchange blockers: theory
and experimental data
Hence attention has focused on limitation of reperfusion injury,
since such interventions could be administered after the onset
of ischemia. This would be practical in patients with myocardial
infarction in whom reperfusion is being considered. In the myocardial
cell, acidosis exerts potent depressive effects on cardiac function
by interfering with excitation-contraction coupling. Accordingly,
there are two major alkalinizing exchangers in the cell that protect
against acidosis: the sodium/hydrogen exchanger (NHE) and the
Na+/HCO3- symporter. There are at least six distinct NHE isoforms,
although NHE1 is ubiquitous and is the predominant one expressed
in the heart.[2] An increase in intracellular
protons activates the NHE. Na+ exchanges for H+ in a 1:1 stoichiometric
relationship until the intracellular pH is restored and then the
exchanger is again inhibited. The steep Na+ gradient across the
membrane supplies energy for extruding protons. During ischemia,
excess protons are produced as mitochondrial oxidation is replaced
with anaerobic glycolysis. As protons accumulate in the cell,
the NHE extrudes H+ in favor of Na+ in an attempt to restore pH.
Because Na+,K+-ATPase is inhibited during ischemia, Na+ increases
as a byproduct of this process. Due to the presence of an Na+/Ca++
exchanger, some Na+ is transported back out of the ischemic cell,
but at the expense of increasing intracellular Ca++. The latter
is felt to be particularly injurious to the cell because of activation
of calcium-dependent proteases and enzymes generating free radicals.
Acidification of the extracellular fluid may limit NHE during
ischemia. At the time of reperfusion, however, the pH of the extracellular
fluid is quickly normalized. Accordingly, there should be an increased
exchange of extracellular Na+ for the accumulated intracellular
H+. The former is then exchanged for Ca++, resulting in accumulation
of potentially damaging Ca++ ions which can uncouple oxidative
phosphorylation in mitochondria,[3] activate
phospholipases leading to membrane damage,[3]
produce abnormalities of myofilament contraction and relaxation,[3]
and initiate after-depolarizations leading to arrhythmias.[4]
Indeed, direct ion measurements[5] and NMR
studies[6,7] have confirmed
these ion shifts in intact hearts. Hence, it was reasoned that
if the NHE could be blocked at reperfusion, cellular Ca++ overload
could be attenuated, and perhaps cellular damage mitigated.
The first NHE blockers, the potassium-sparing diuretic amiloride
and its derivatives, were indeed found to be protective in experimental
animals. They preserved postischemic ventricular function[3,5,6,8–10]
and diminished myocardial enzyme release.[8–11]
Although protection was greatest when the drug was administered
before ischemia,[3,5,6,8–12]
in many studies protection was still evident even when treatment
was delayed until just before reperfusion.[5,9,10,12]
Unfortunately, these drugs were not specific for NHE. The newer
NHE antagonists, however, are both potent and specific. One of
these is cariporide. In experimental animals it decreases ischemic
and reperfusion arrhythmias,[13–16] decreases
enzyme release following ischemia,[13] diminishes
infarct size,[15,17–20]
and limits apoptosis.[16,21]
These cardioprotective effects were clearly seen when cariporide
was infused intravenously before ischemia,[13–19,21]
and again, in some studies, protection was also seen when infusion
was delayed until after the onset of ischemia[20]
and even until shortly before reperfusion.[15,19]
NHE clinical trials: Guardian and Escami
Because of the solid theory behind the cardioprotective effect
of NHE blockers and the impressive experimental data obtained
with cariporide, a clinical trial, GUARDIAN (Guard During Ischemia
Against Necrosis), was organized.[22] This
was an international, combined phase-II/phase-III dosing, safety,
and efficacy trial in which 11,590 subjects with acute coronary
syndromes at risk for myocardial infarction were enrolled. There
were three clinical arms: (1) unstable angina or non-ST-segment
elevation myocardial infarction; (2) high-risk angioplasty; and
(3) urgent, repeat, or high-risk coronary revascularization surgery.
Patients were randomized to receive either intravenous placebo
or 20, 80, or 120 mg cariporide tid. Drug infusion was initiated
shortly before the procedure or as soon as the clinical diagnosis
was made and was generally continued for 2–7 days. Primary endpoints
were the incidence of myocardial infarction and mortality at 36
days after randomization, while secondary endpoints were the appearance
of events related to left ventricular dysfunction such as heart
failure and shock at 6 months, and extent of infarction assessed
by peak levels of CK-MB.
The results were disappointing. For all patients there was no
benefit of cariporide over placebo for primary endpoints. Only
one of the nine cariporide subgroups showed diminished risk. There
was no effect at any dose in the unstable angina subgroup. A 23%
decrease in risk in the angioplasty group treated with 20 mg tid
barely missed significance (P = 0.06), but there was no effect
at the higher doses. There was also no effect of 20 and 80 mg
doses in the surgical group. Only at 120 mg tid was the 25% decrease
in risk of myocardial infarction and death following surgery significant
(P = 0.027). Mortality by itself was unaffected. Q-wave myocardial
infarctions were decreased in all groups. Non-Q-wave infarctions
were diminished by 47% in the surgical subjects treated with 120
mg tid (P = 0.005), but not in the other two surgical subgroups.
An encouraging note was the absence of any significant clinical
adverse effects.
There are clearly some tantalizing observations. Because there
was decreased risk in the surgical subgroup treated with the highest
dose of 120 mg tid, it is reasonable to suspect that the other
subjects were underdosed. The drug appeared to be safe at the
doses used, so higher doses could be explored. A likely explanation
for these results is that the most significant portion of the
sodium-hydrogen exchange takes place during ischemia as opposed
to reperfusion. Thus, only groups that had the luxury of pretreatment
would have benefitted. Furthermore it is unlikely that the clinical
group with unstable angina would have derived any significant
benefit from cariporide because of the absence of prolonged ischemia
and subsequent reperfusion. So the question of the ultimate value
of NHE blockers is still unanswered. Interestingly ESCAMI (Evaluation
of the Safety and Cardioprotective Effects of Eniporide in Acute
Myocardial Infarction), a phase-II clinical trial with another
selective NHE blocker eniporide, also showed no beneficial clinical
effects in patients with acute myocardial infarction, and Merck
KGaA has decided to discontinue development of eniporide for this
indication.
Adenosine at reperfusion – clinical trial:
AMISTAD
Adenosine has also been tested for its ability to reduce clinical
reperfusion injury. Pretreatment with adenosine is known to protect
the heart through the preconditioning mechanism.[1,23]
However, its effect on reperfusion injury is controversial. Whereas
some investigators including ourselves have been unable to demonstrate
any effect of adenosine or selective adenosine receptor agonists
on infarct size when administered shortly before reperfusion,[24–26]
others have.[27–29] Proponents of an adenosine
effect suggest this purine can replenish high-energy phosphate
stores in endothelial cells and myocytes, inhibit oxygen free
radical production, inhibit neutrophil activity and accumulation,
and improve microvascular function. On the basis of these latter
data a clinical trial AMISTAD (Acute Myocardial Infarction Study
of Adenosine) was organized.[30] This was a
small, open-label trial of thrombolysis in patients with myocardial
infarction and acute ST-segment elevation. Patients were randomized
to either placebo or intravenous adenosine (70 mg/kg per min for
3 h) starting shortly before or after infusion of the thrombolytic
agent. The primary endpoint was infarct size measured with Tc-99m
sestamibi SPECT 5–7 days after enrollment.
A secondary endpoint was a composite of in-hospital clinical outcomes
(mortality, reinfarction, shock, heart failure, stroke).
Two hundred thirty-six patients were enrolled and the results
were mixed but provocative. For all patients, the 33% relative
decrease in infarct size following treatment with adenosine was
not significant (P = 0.085); but when infarctions were subdivided
into anterior and nonanterior, differences became apparent. The
67% relative decrease in infarct size in those with anterior infarction
treated with adenosine was significant (P = 0.014), whereas infarct
size was not affected by the presence of adenosine in those with
other than anterior infarction. On the negative side, there was
a nonsignificant excess of deaths, reinfarctions, heart failure,
and cardiogenic shock in patients treated with adenosine. The
composite endpoint was reached in 18% of the adenosine group and
14% of the placebo group (odds ratio 1.43).
Thus there was a likely benefit of adenosine in reducing infarct
size only in patients with anterior infarction. Perhaps the larger
size of the anterior infarctions gave adenosine a better chance
to yield a positive effect. However, the small size of the groups
raises the specter of a type II statistical error. It is also
unsettling that there was a tendency for those subjects treated
with adenosine to have more adverse clinical events. A very small
subset of the patients had baseline perfusion scans to measure
the size of the risk area. Only in these patients could actual
myocardial salvage be estimated. Clearly, a measure of salvage
would be a better gauge of an antiinfarct effect than determination
of absolute infarct size. Medco has undertaken a phase-III trial
of adenosine in acute myocardial infarction, AMISTAD II, in which
approximately 2100 patients will be treated in 300 centers in
the US and Canada. Data should be available next year.
It is certainly much more difficult to prove efficacy of a treatment
in man than in experimental animals. Clinical trials require hundreds
and even thousands of patients and are costly. But this translational
research is critical if we are to continue to improve clinical
strategies for the care of patients with acute coronary syndrome.
Adjunctive reperfusion therapy seems to be a good idea, but we
have yet to identify the ideal agent.
REFERENCES
-
Ischemic preconditioning: from adenosine receptor of KATP
channel.
Cohen MV, Baines CP, Downey JM.
Department of Medicine, University of South Alabama, College
of Medicine, Mobile 36688, USA. mcohen@usamail.usouthal.edu
Ischemic preconditioning is a phenomenon whereby exposure of
the myocardium to a brief episode of ischemia and reperfusion
markedly reduces tissue necrosis induced by a subsequent prolonged
ischemia. It is hoped that elucidation of the mechanism for
preconditioning will yield therapeutic strategies capable of
reducing myocardial infarction. In the rabbit, the brief period
of preconditioning ischemia and reperfusion releases adenosine,
bradykinin, opioids, and oxygen radicals. The combined effect
of the release of these substances on G proteins and the cell's
phospholipases induces the translocation and activation of the
epsilon isozyme of protein kinase C. Protein kinase C appears
to be the first element of a complex kinase cascade that is
activated during the prolonged ischemia in preconditioned hearts.
Current evidence indicates that this cascade contains at least
one tyrosine kinase and ultimately leads to the activation of
p38 mitogen-activated protein kinase. p38 Mitogen-activated
protein kinase phosphorylates mitogen-activated protein kinase-activated
protein kinase 2. Mitogen-activated protein kinase-activated
protein kinase 2 phosphorylates HSP27, a 27-kDa heat shock protein
that controls actin filament polymerization, and, therefore,
affects the integrity of the cytoskeleton. Finally, mitochondrial
adenosine 5'-triphosphate-sensitive K+ channels open, and the
latter may be the final mediator of protection for ischemic
preconditioning. The protective pathway has many built-in redundancies,
perhaps creating a safety factor. These redundancies may also
explain some of the species-related differences seen in ischemic
preconditioning in which one redundant pathway may predominate
over another.
Publication Types:
 |
Review
|
|
Review, academic |
PMID: 10845085 [PubMed - indexed for MEDLINE]
-
-
Molecular physiology of vertebrate Na+/H+ exchangers.
Wakabayashi S, Shigekawa M, Pouyssegur J.
Department of Molecular Physiology, National Cardiovascular
Center Research Institute, Osaka, Japan.
This review describes recent progress concerning the molecular
aspects of the Na+/H+ exchanger. The Na+/H+ exchanger is an
important regulator for intracellular pH, cell volume, and transepithelial
Na+ transport. It exists in virtually all cells with cell type-dependent
pattern of isoform expression, and it is regulated in response
to a variety of extracellular stimuli, among them not only agonists
such as growth factors and hormones but also mechanical stimuli
such as osmotic stress and cell spreading. Thus this transporter
is also an excellent model to study the signal transduction.
Since the first molecular cloning of the Na+/H+ exchanger, detailed
studies revealed many interesting features of this transporter.
At present, at least five different isoforms of the Na+/H+ exchanger
are known. These isoforms differ in tissue localization, sensitivity
of inhibitors, and mode of transcriptional and posttranscriptional
regulation, allowing them to participate in different physiological
processes. We have only started to understand an intriguing
mechanism underlying these functional differences among the
exchanger isoforms. Because the Na+/H+ exchanger is relatively
simple in terms of its kinetic features, e.g., a simple 1:1
stoichiometry of Na+ and H+ and no input of metabolic energy
such as ATP hydrolysis, the study of its structural and mechanistic
aspects would also serve as a good model to understand the general
mechanism of various ion transporters.
Publication Types:
|
Review
|
|
Review, academic |
PMID: 9016300 [PubMed - indexed for MEDLINE]
-
Sodium-hydrogen exchange inhibitors improve postischemic
recovery of function in the perfused rabbit heart.
Myers ML, Mathur S, Li GH, Karmazyn M.
University of Western Ontario, London, Canada.
OBJECTIVE: The aim was to examine the effects of the Na+/H+
exchange inhibitors amiloride and methylisobutyl amiloride (MIA)
in buffer perfused rabbit hearts subjected to one hour of normothermic
ischaemia (37 degrees C) followed by reperfusion. METHODS: Experiments
were carried out in five groups of Langendorff perfused rabbit
hearts: (1) control, (2) amiloride, and (3) MIA (agents in both
the preischaemic and reperfusion perfusate), (4) amiloride-R
and (5) MIA-R (agents added at reperfusion only). Functional
evaluation included serial measurement of resting tension, force,
rates of ventricular force development and relaxation, and coronary
perfusion pressure. Samples of coronary effluent were obtained
for creatine kinase assay and hearts were freeze clamped for
metabolite assays. RESULTS: Reperfusion resulted in a marked
increase in resting tension in group (1) which was statistically
significant compared to groups (2) and (3). Groups (2) and (3)
also showed significantly improved recovery of ventricular force,
rate of force development, and rate of ventricular relaxation.
Addition of either agent only during reperfusion failed to produce
a significant beneficial effect. There were no significant differences
among the groups with respect to postreperfusion creatine kinase
release or end reperfusion metabolite levels. CONCLUSION: This
study shows for the first time that both of the Na+/H+ exchange
inhibitors amiloride and MIA produce improved recovery of ventricular
function in rabbit hearts subjected to ischaemia and reperfusion,
although the beneficial effect was not obtained with drug administration
at the time of reperfusion only.
PMID: 7736497 [PubMed - indexed for MEDLINE]-
Intracellular calcium transients and arrhythmia in isolated
heart cells.
Thandroyen FT, Morris AC, Hagler HK, Ziman B, Pai L, Willerson
JT, Buja LM.
Department of Internal Medicine Cardiology, University of Texas
Southwestern Medical Center, Dallas.
Intracellular calcium ([Ca2+]i) elevation may mediate cardiac
arrhythmias. However, direct measurement of the rapid alterations
of [Ca2+]i on a beat-to-beat basis using fast temporal resolution
and without signal averaging in the spontaneously beating in
vivo heart is lacking. Furthermore, data from an isolated spontaneously
beating myocyte preparation that develops arrhythmia similar
to that in the in vivo heart are unavailable. We measured rapid
changes of [Ca2+]i with fast temporal resolution in isolated
spontaneously beating neonatal rat ventricular myocytes with
cell-to-cell communication and characterized the interrelation
between [Ca2+]i and arrhythmia. An elevated extracellular calcium
([Ca2+]o) concentration of 10.8 mM induced premature beats,
a rapid beating rate (tachyarrhythmia), and chaotic or fibrillatory
beating activity in a small group of myocytes. [Ca2+]i levels
during systole increased from the nanomolar to micromolar concentration
range before arrhythmia development. Spontaneous oscillations
of [Ca2+]i during diastole could evoke a spontaneous tachyarrhythmia.
In the presence of [Ca2+]i elevation, a spontaneous tachyarrhythmia
could induce severe [Ca2+]i overload. Reduction of [Ca2+]i with
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid AM
(5 microM) in the presence of 10.8 mM [Ca2+]o reversed the arrhythmia.
In single ventricular myocytes superfused with 10.8 mM [Ca2+]o,
oscillations of membrane potential characteristic of transient
inward current occurred that were prevented by ryanodine (0.1
microM), an inhibitor of Ca2+ flux across the sarcoplasmic reticulum.
This study characterizes 1) an isolated multicellular myocyte
model of arrhythmia similar to that evident in in vivo hearts,
2) elevation of [Ca2+]i with systolic [Ca2+]i levels of 1-3
microM and diastolic [Ca2+]i oscillations before the initiation
of arrhythmia, 3) tachyarrhythmia as a cause of severe [Ca2+]i
overload, which may be important in the perpetuation and degeneration
of arrhythmias, and 4) reversal of arrhythmia with reduction
of [Ca2+]i. The results in the isolated myocyte model may have
relevance to the generation and perpetuation of certain cardiac
arrhythmias associated with calcium overload.
PMID: 1873874 [PubMed - indexed for MEDLINE]
-
Role of intracellular Na+ in Ca2+ overload and depressed
recovery of ventricular function of reperfused ischemic rat
hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange.
Tani M, Neely JR.
Sigfried and Janet Weis Center for Research, Geisinger Clinic,
Danville, Pennsylvania.
The roles of H+-Na+ and Na+-Ca2+ exchange in the depression
of ventricular function were studied in the reperfused isolated
ischemic rat heart. Zero-flow global ischemia was induced for
either 15 or 30 minutes and was followed by 30 minutes of aerobic
reperfusion. Intracellular Na+ (Na+i) and 45Ca2+ uptake were
measured during ischemia and reperfusion. Accumulation of Na+i
was modified by prior glycogen depletion and by treatment with
amiloride, a H+-Na+ exchange inhibitor, or monensin, a Na+ ionophore.
Na+i rose continuously during ischemia and rapidly during the
first two minutes of reperfusion. The larger inhibitory effect
of amiloride and preischemic glycogen depletion was on Na+i
accumulation during reperfusion; this finding suggests that
the uptake occurs by H+-Na+ exchange. Reduction of Na+i accumulation
by glycogen depletion was associated with less lactate and,
presumably, H+ production and accumulation during ischemia.
The rapid increase in Na+i during early reperfusion may reflect
the readjustment of the low intracellular pH resulting from
ischemia. The level of Na+i at the end of ischemia and especially
after two minutes of reperfusion were linearly correlated with
45Ca2+ uptake and depression of ventricular function during
subsequent reperfusion. This highly significant correlation
between Na+i and 45Ca2+ uptake when Na+i was varied by several
independent procedures, including monensin, strongly suggests
that reperfusion 45Ca2+ uptake occurs at least in part by Na+-Ca2+
exchange. The rate of 45Ca2+ uptake during reperfusion was linearly
and highly significantly correlated with elevation of diastolic
pressure, reduced developed pressure, and decreased recovery
of ventricular function. The data strongly support a mechanism
of ischemic cell damage that involves excessive production and
accumulation of H+ during ischemia that exchanges for extracellular
Na+ during ischemia and rapidly during the first few minutes
of reperfusion. Increased Na+i then causes excessive 45Ca2+
uptake and depressed recovery of cellular functions with continued
reperfusion. Increased levels of Na+i may be a major event that
couples a decreased intracellular pH during ischemia to excessive
45Ca2+ uptake and depressed recovery of cellular function with
reperfusion.
PMID: 2551525 [PubMed - indexed for MEDLINE]-
NMR measurements of Na+ and cellular energy in ischemic rat
heart: role of Na(+)-H+ exchange.
Pike MM, Luo CS, Clark MD, Kirk KA, Kitakaze M, Madden MC,
Cragoe EJ Jr, Pohost GM.
Department of Medicine, University of Alabama at Birmingham
35294.
Interleaved 23Na- and 31P-nuclear magnetic resonance (NMR) spectra
were continuously collected on perfused rat hearts subjected
to low-flow ischemia (30 min, 10% flow) or zero-flow ischemia
(21 min) followed by reperfusion. During untreated low-flow
and zero-flow ischemia, intracellular Na+ (Nai+) increased by
53 +/- 11 (+/- SE) and 78 +/- 8%, respectively, and remained
elevated for zero-flow hearts. However, during both low- and
zero-flow ischemia, Nai+ did not increase in hearts treated
with the Na(+)-H+ exchange inhibitor, 5-(N-ethyl-N-isopropyl)amiloride
(EIPA). The pH decreases during ischemia were unchanged. EIPA
treatment reduced ATP depletion during ischemia. During reperfusion
from zero-flow ischemia, EIPA-treated hearts displayed more
rapid and extensive recoveries of phosphocreatine and ATP. Recovery
of left ventricular developed pressure was improved for zero-flow
hearts treated with EIPA during the ischemic period exclusively
(104 +/- 13%) compared with untreated hearts (36 +/- 21%). These
data indicate that Na(+)-H+ exchange is an important mechanism
for Nai+ accumulation, but not for pH regulation, during myocardial
ischemia. Additionally, Nai+ homeostasis plays an important
role in the postischemic recovery of cellular energy and ventricular
function.
PMID: 8285240 [PubMed - indexed for MEDLINE]
-
-
Activity of the Na+/H+ exchanger contributes to cardiac damage
following ischaemia and reperfusion.
Allen DG, Xiao XH.
Institute for Biomedical Research, Department of Physiology,
University, of Sydney, New South Wales, Australia. davida@physiol.usyd.edu.au
1. The present review considers the evidence that Na+-H+ exchange
activity contributes to cardiac damage following ischaemia and
reperfusion. The basic mechanism involved is that protons are
produced during ischaemia and leave the myocytes on the Na+/H+
exchanger during either ischaemia and/or reperfusion. The resulting
elevation of [Na+]i causes Ca2+ loading through the Na+/Ca2+
exchanger and the elevated [Ca2+]i is thought to lead to myocardial
damage. 2. Inhibition of the Na+/H+ exchanger during ischaemia
and/or reperfusion produces a substantial cardioprotective effect
by blocking the damage caused by the coupled exchanger mechanism
described above. Preconditioning also produces a cardioprotective
effect and the evidence that this also involves the Na+/H+ exchanger
is reviewed. 3. The intracellular mechanisms associated with
ischaemic damage and preconditioning are of great interest because
they may provide targets for potential therapeutic interventions.
The intracellular regulation of the Na+/H+ exchanger appears
to be an important component of these pathways and may become
a focus for therapeutic approaches.
Publication Types:
|
Review
|
|
Review, tutorial |
PMID: 10972541 [PubMed - indexed for MEDLINE]
-
Amiloride enhances postischemic ventricular recovery: possible
role of Na+-H+ exchange.
Karmazyn M.
Department of Pharmacology, Faculty of Medicine, Dalhousie University,
Halifax, Nova Scotia, Canada.
Amiloride (40 micrograms/ml) was studied in the isolated rat
heart subjected to low-flow ischemia followed by reperfusion.
Reperfusion after 30 min of ischemia produced recoveries of
force, rate of force development (+dF/dt), and rate of relaxation
(-dF/dt) of 42, 82, and 71%, respectively, in control hearts.
Amiloride did not enhance the maximum degree of recovery, although,
when present during ischemia, it markedly shortened the time
required for peak recovery. Reperfusion after 60 min of ischemia
resulted in 18, 43, and 34% recovery of force, +dF/dt, and -dF/dt,
respectively. Amiloride significantly enhanced recovery to a
maximum of 39, 88, and 78% for force, +dF/dt, and -dF/dt, respectively.
The improved contractile recovery was accompanied with substantial
reductions in the release of creatine kinase (CK) and 6-ketoprostaglandin
F1 alpha. Coronary perfusion pressure and resting tension were
generally unaffected by amiloride, although there was a moderate
tendency to attenuate these parameters after reperfusion. The
salutary effects of amiloride were dependent on the drug's presence
during ischemia with maximum protection when it was administered
during both ischemia and reperfusion and no benefit when added
at the time of reperfusion. Because of amiloride's well-documented
property in inhibiting Na+-H+ exchange, it is possible that
this process plays an important role in modulating the cardiac
response to reperfusion.
PMID: 2843057 [PubMed - indexed for MEDLINE]
-
Protective effects of 5-(N,N-dimethyl)amiloride on ischemia-reperfusion
injury in hearts.
Meng HP, Pierce GN.
Division of Cardiovascular Sciences, St. Boniface General Hospital
Research Center, Winnipeg, Manitoba, Canada.
An Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA),
was used to probe the possible role of Na(+)-H+ exchange in
ischemia-reperfusion injury in coronary perfused isolated rat
right ventricular wall. In DMA-untreated hearts, 60 min of ischemia
resulted in a significant rise in testing tension (RT: 174 +/-
8% of preischemic level). Thirty minutes of reperfusion further
increased RT (273 +/- 12%) and induced a poor recovery in developed
tension (DT: 28 +/- 4%). Both the rate of tension development
and relaxation (+dT/dt and -dT/dt) recovered to a similar degree.
When 1, 5, or 20 microM DMA was included in the perfusate (3
min before ischemia and in the first 3 min of reperfusion),
the maximal postischemic RT of the heart was reduced to 204
+/- 21, 166 +/- 15, and 139 +/- 45% of the preischemic levels
(P less than 0.05), respectively, and DT was 39 +/- 3, 63 +/-
10, and 79 +/- 8% of the preischemic levels (P less than 0.05),
respectively. Similar qualitative recovery of +/- dT/dt was
observed. Recovery was similar if DMA was present only during
reperfusion. DMA treatment also significantly protected against
creatine phosphokinase release during reperfusion. The results
demonstrate that DMA can significantly protect the heart during
the initial stages of reperfusion. The data suggest that Na(+)-H+
exchange may play an important role in the development of cardiac
dysfunction and damage during the first minutes of reperfusion.
PMID: 2337191 [PubMed - indexed for MEDLINE]
-
Effects of amiloride and an analogue on ventricular arrhythmias,
contracture and cellular injury during reperfusion in isolated
and perfused guinea pig heart.
Otani H, Kato Y, Ko T, Sakurai Y, Kagawa K, Tanaka K, Fukunaka
M, Imamura H, Cragoe EJ Jr.
Department of Thoracic and Cardiovascular Surgery, Kansai Medical
University, Osaka, Japan.
The present study was designed to examine whether activation
of Na+/H+ exchange and subsequent massive Ca2+ influx via Na+/Ca2+
exchange are involved in the pathogenesis of myocardial reperfusion
injury. We tested the effects of 1 mM amiloride, which is known
to inhibit both Na+/H+ and Na+/Ca2+ exchange, and 3 microM 5-(N-ethyl-N-isopropyl)
amiloride (EIPA), which is known to act as a specific inhibitor
against Na+/H+ exchange, on the incidence of ventricular arrhythmias,
isovolumic left ventricular function and creatine kinase (CK)
release during reperfusion after 15 or 30 min of global ischemia
in the isolated and perfused guinea pig heart. Treatment of
a normally perfused heart with amiloride decreased heart rate
significantly and tended to increase coronary flow and left
ventricular developed pressure (LVDP), whereas treatment with
EIPA decreased all of these 3 measurements significantly. Treatment
with amiloride or EIPA for 15 min before ischemia, and during
reperfusion after 15 min of ischemia, under electrical pacing
at 240 rpm to eliminate a negative chronotropic effect abolished
ventricular tachycardia (VT) and ventricular fibrillation (VF)
during reperfusion associated with highly significant inhibition
of increases in left ventricular end-diastolic pressure (LVEDP)
and CK release. Amiloride or EIPA pretreatment also inhibited
the incidence of VF and increases in LVEDP and CK release significantly
during reperfusion after 30 min of ischemia. However, amiloride
was more effective in preventing these events than EIPA. The
treatment with amiloride or EIPA only during reperfusion after
15 or 30 min of ischemia also decreased the incidence of VF
and inhibited the increases in LVEDP and CK release significantly,
though less effectively than the pretreatment modality. These
results suggest that EIPA prevents ventricular arrhythmias,
contracture and myocardial cellular injury during reperfusion
after 15 min of ischemia by inhibiting Na+/H+ exchange, while
amiloride exerts more powerful protection against these events
than EIPA during reperfusion after 30 min of ischemia by inhibiting
both Na+/H+ and Na+/Ca2+ exchange.
PMID: 1942491 [PubMed - indexed for MEDLINE]
-
Effects of Na+/H+ exchange inhibitors in cardiac ischemia.
Scholz W, Albus U, Linz W, Martorana P, Lang HJ, Scholkens
BA.
Hoechst AG, Frankfurt/M., Germany.
To investigate a possible protective role of Na+/H+ exchange
inhibition under ischemic conditions isolated rat hearts were
subjected to regional ischemia and reperfusion. In these experiments
all 6 untreated hearts suffered ventricular fibrillation on
reperfusion. Addition of 1 x 10(-5) mol/l amiloride or 3 x 10(-7)
mol/l 5-(N-ethyl-N-isopropyl)amiloride (EIPA) markedly decreased
the incidence and duration of ventricular fibrillation or even
suppressed fibrillation completely as in the case of 1 x 10(-6)
mol/l EIPA. Both compounds diminished the activities of lactate
dehydrogenase and creatine kinase in the venous effluent of
the hearts during ischemia. At the end of the experiments tissue
contents of glycogen, ATP and creatine phosphate were increased
in the treated hearts as compared to control hearts. In an additional
experiment the beneficial effects of Na+/H+ exchange inhibition
during ischemia was confirmed in vivo with anaesthetized rats
undergoing coronary artery ligation. In these animals amiloride
or EIPA pretreatment caused a marked reduction of ventricular
premature beats and ventricular tachycardia as well as a complete
suppression of ventricular fibrillation. The concentration dependent
inhibition of Na+ influx via Na+/H+ exchange by amiloride and
EIPA was investigated in erythrocytes from hypercholesterolemic
rabbits with Na+/H+ exchange activated by exposure to hyperosmotic
medium. Furthermore the inhibition of Na+ influx by EIPA after
intracellular acidification was studied in cardiac myocytes
of neonatal rats. Both agents were effective in the same order
of potency in the ischemic isolated working rat heart as in
the erythrocyte model in which they inhibited Na+/H+ exchange.(ABSTRACT
TRUNCATED AT 250 WORDS)
PMID: 1328656 [PubMed - indexed for MEDLINE]
-
Na+/H+ exchange and reperfusion arrhythmias: protection by
intracoronary infusion of a novel inhibitor.
Yasutake M, Ibuki C, Hearse DJ, Avkiran M.
Rayne Institute, St. Thomas' Hospital, London, United Kingdom.
Activation of sarcolemmal Na+/H+ exchange has been proposed
as a causal factor in reperfusion arrhythmogenesis. To test
this hypothesis, we determined the antiarrhythmic efficacy of
two structurally distinct but equipotent Na+H+ exchange inhibitors,
5-(N-ethyl-N-isopropyl)amiloride (EIPA) and the novel drug,
3-methylsulfonyl-4-piperidinobenzoyl guanidine (HOE-694), in
isolated rat hearts (n = 12/group) subjected to independent
dual coronary perfusion. After 15 min of aerobic perfusion of
both beds, flow to the left coronary bed (LCB) was terminated
for 10 min; this was followed by 5 min of reperfusion. Various
concentrations of each drug were selectively infused into the
LCB either during the 5-min period preceding ischemia plus during
reperfusion or during reperfusion alone. With the former protocol,
0.01, 0.1, 1, and 10 microM EIPA reduced the incidence of reperfusion-induced
ventricular fibrillation (VF) from 92% in controls to 83, 83,
50, and 0% (P < 0.05); the number of hearts in sinus rhythm
at the end of reperfusion was increased from 17 to 42, 25, 83
(P < 0.05), and 100% (P < 0.05). HOE-694, at the same
concentrations, reduced VF incidence from 92% in control to
83, 58, 50, and 8% (P < 0.05); 25, 67, 75 (P < 0.05),
and 100% (P < 0.05) of hearts were in sinus rhythm, compared
with 17% of controls, at the end of reperfusion. Even when infused
during reperfusion alone, both drugs afforded significant protection
against reperfusion-induced VF, which did not differ significantly
from that observed when the drugs were also given before ischemia.
The similar antiarrhythmic efficacy of EIPA and HOE-694 is consistent
with an arrhythmogenic role for activation of Na+/H+ exchange
during early reperfusion.
PMID: 7810741 [PubMed - indexed for MEDLINE]
-
Protective effects of HOE642, a selective sodium-hydrogen
exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion.
Scholz W, Albus U, Counillon L, Gogelein H, Lang HJ, Linz
W, Weichert A, Scholkens BA.
Hoechst AG, Cardiovascular Research H 821, Frankfurt/Main, Germany.
OBJECTIVE: The aim was to characterise the new compound HOE642
as a selective and cardioprotective Na+/H+ exchange inhibitor
in various models. METHODS: The effect of HOE642 was tested
in the osmotically activated Na+/H+ exchange of rabbit erythrocytes
and in propionate induced swelling of human thrombocytes. Recovery
of pH after an NH4Cl prepulse and effects on other ion transport
systems by patch clamp technique were investigated in rat cardiomyocytes.
NHE subtype specifity of the compound was determined by 22Na+
uptake inhibition in a fibroblast cell line separately expressing
subtype isoforms 1-3. Protective effects of HOE642 in cardiac
ischaemia and reperfusion by ligation of coronary artery were
investigated in isolated working rat hearts and in anaesthetised
rats. RESULTS: HOE642 concentration dependently inhibited the
amiloride sensitive sodium influx in rabbit erythrocytes, reduced
the swelling of human platelets induced by intracellular acidification,
and delayed pH recovery in rat cardiomyocytes. In the isolated
working rat heart subjected to ischaemia and reperfusion HOE642
dose dependently reduced the incidence and the duration of reperfusion
arrhythmias. It also reduced the the release of lactate dehydrogenase
and creatine kinase, and preserved the tissue content of glycogen,
ATP, and creatine phosphate. In anaesthetised rats undergoing
coronary artery ligation intravenous and oral pretreatment with
HOE642 caused a dose dependent reduction or a complete prevention
of ventricular premature beats, ventricular tachycardia, and
ventricular fibrillation. The compound was well tolerated and
neutral to circulatory variables. Other cardiovascular agents
tested in this model were not, or were only partly, effective
at doses showing marked cardiodepressive effects. CONCLUSIONS:
HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective
and antiarrhythmic effects in ischaemic and reperfused hearts.
Further development of well tolerated compounds like HOE642
could lead to a new therapeutic approach in clinical indications
related to cardiac ischaemia and reperfusion.
PMID: 7736504 [PubMed - indexed for MEDLINE]
-
Antiarrhythmic effects of HOE642, a novel Na(+)-H+ exchange
inhibitor, on ventricular arrhythmias in animal hearts.
Xue YX, Aye NN, Hashimoto K.
Department of Pharmacology, Yamanashi Medical University, Japan.
HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate),
a novel Na(+)-H+ exchange subtype 1 inhibitor, was investigated
for its possible antiarrhythmic effects on coronary artery ligation/reperfusion
and ouabain-induced arrhythmias in the canine heart which may
occur after intracellular Ca2+ overload. Also, the effects of
HOE642 on coronary artery ligation/reperfusion of the left coronary
artery were tested in rat hearts. HOE642 (1 mg/kg) significantly
suppressed the occurrence of fatal ventricular fibrillation
during coronary artery ligation and after reperfusion in dogs
(2 out of 8 dogs in the treated group compared to 7 out of 8
dogs in the control group, P < 0.05), but did not suppress
ventricular premature contractions and ventricular tachycardia
during ischemia in the canine hearts. HOE642 at the same dose
markedly reduced the total duration and the incidence of reperfusion-induced
ventricular tachycardia, and the incidence and mortality of
reperfusion-induced ventricular fibrillation in rats (ventricular
tachycardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01;
ventricular tachycardia, 100% to 69%; ventricular fibrillation,
89% to 0%, P < 0.01; mortality, 89% to 11%, P < 0.01).
The heart rate, blood pressure, QT interval and ST segment did
not change in the canine and rat hearts. HOE642 slightly decreased
the arrhythmic ratio of the ouabain-induced arrhythmia only
at two time points (28 and 35 min after injection) in the canine
hearts. In conclusion, HOE642 has obvious antifibrillatory effects
on ischemia/reperfusion arrhythmias and, in addition, has a
weak suppressing effect on the ouabain-induced arrhythmia.
PMID: 8997615 [PubMed - indexed for MEDLINE]
-
Prevention of ischemic rigor contracture during coronary
occlusion by inhibition of Na(+)-H+ exchange.
Garcia-Dorado D, Gonzalez MA, Barrabes JA, Ruiz-Meana M,
Solares J, Lidon RM, Blanco J, Puigfel Y, Piper HM, Soler-Soler
J.
Servicio de Cardiologia, Hospital General Universitari Vall
d'Hebron, Barcelona, Spain. dgdorado@ar.vhebron.es
OBJECTIVE: To determine the effect of Na(+)-H+ exchange blockade
on ischemic rigor contracture and reperfusion-induced hypercontracture.
METHODS: Thirty-six pigs were submitted to 55 min of coronary
occlusion and 5 h reperfusion. Myocardial segment length analysis
with ultrasonic microcrystals was used to detect ischemic rigor
(reduction in passive segment length change) and hypercontracture
(reduction in end-diastolic length). RESULTS: Pretreatment with
the new, highly selective Na(+)-H+ exchange inhibitor HOE642
before occlusion reduced ischemic rigor (P < 0.05), attenuated
segment shrinkage (P < 0.05) during subsequent reperfusion,
dramatically reduced infarct size (P < 0.0001) and attenuated
arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only
during reperfusion by means of direct intracoronary infusion
of HOE642 into the area at risk prevented reperfusion arrhythmias
but had no effect on final infarct size, while treatment with
intravenous HOE642 immediately before reperfusion had no detectable
effects. CONCLUSION: These results indicate that inhibition
of Na(+)-H+ exchange during ischemia is necessary to limit myocardial
necrosis secondary to transient coronary occlusion, and that
this action could by mediated by a protective effect against
ischemic contracture. Inhibition of Na(+)-H+ exchange only during
reperfusion has a partial and transient beneficial effect, but
only when the inhibitor reaches the area at risk before reflow.
PMID: 9302350 [PubMed - indexed for MEDLINE]
-
Orally administered NHE1 inhibitor cariporide reduces acute
responses to coronary occlusion and reperfusion.
Humphreys RA, Haist JV, Chakrabarti S, Feng Q, Arnold JM,
Karmazyn M.
Department of Pharmacology and Toxicology, University of Western
Ontario, London, Ontario, Canada N6A 5C1.
Na+/H+ exchange (NHE) mediates myocardial ischemic and reperfusion
injury. We examined the effects of dietary administration of
the potent and selective NHE1 inhibitor cariporide on acute
responses to coronary artery ligation and reperfusion in the
anesthetized rat. Male Sprague-Dawley rats received control
rat chow or an identical diet containing 3 parts per million
of cariporide for 1 wk before 225 min of occlusion of the left
main coronary artery or 45 min of occlusion followed by 180
min of reperfusion. Hearts were excised and divided into left
ventricle, right ventricle, and interventricular septum for
analysis of NHE1 mRNA expression and apoptosis by staining with
terminal deoxynucleotidyl transferase-mediated nick end labeling.
Ischemia and reperfusion were associated with a threefold elevation
in NHE1 mRNA expression in control animals that was significantly
reduced in cariporide-fed rats. Cariporide reduced mortality
from 26% of animals to 0%. The incidence of all arrhythmias
was significantly reduced, including ventricular fibrillation
(from 42 to 0%) and ventricular tachycardia (from 81 to 15%),
as well as the number of ventricular premature beats (from 70
+/- 12 to 17 +/- 6). Cariporide moderately reduced apoptosis
only in the reperfused left ventricle to values not significantly
greater than those in sham-operated animals, and this was associated
with a significantly higher ratio of Bcl-2 to Bax. This study
suggests that NHE inhibition with dietary cariporide represents
an effective management of acute postinfarction responses.
PMID: 9950878 [PubMed - indexed for MEDLINE]
-
Time delay of cell death by Na+/H+-exchange inhibition in
regionally ischemic, reperfused porcine hearts.
Klein HH, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber
J, Nebendahl K.
Division of Cardiology, Stadt. Krankenanstalten Idar-Oberstein
GmbH, Germany.
Studies in different preparations have suggested that Na+/H+
exchange is one mechanism causally involved in cell death in
myocardial ischemia and reperfusion. The time delay of cell
death by pretreatment with the Na+/H+-exchange inhibitor HOE642,
cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate),
was investigated in regionally ischemic, reperfused porcine
hearts. HOE642 (1 mg/kg) was injected intravenously in 14 thoracotomized
pigs 10 min before occlusion of the left anterior descending
coronary artery (45 min of ischemia, six pigs; 70 min of ischemia,
six pigs; 90 min of ischemia, two pigs). Ischemia was followed
by 24 h of reperfusion. Six animals (45 min of ischemia) served
as controls. Infarct size was determined as a ratio of infarcted
(tetrazolium stain, histology) to ischemic myocardium (dye technique),
and regional myocardial function was assessed by sonomicrometry.
HOE642 did not affect global hemodynamic parameters. In the
pretreated group with 45 min of ischemia, HOE642 significantly
decreased histochemical infarct size from 51.2 +/- 12.6% (control
group) to 13.2 +/- 12% (p < 0.005) and histologic infarct
size from 44.5 +/- 9% to 17.1 +/- 7% (p < 0.005). Recovery
of regional systolic shortening after 24 h of reperfusion was
improved from 2 +/- 6% (control group) to 12 +/- 7% (p = 0.02).
In addition, myocardial contracture and increase in heart rate
during early reperfusion were attenuated. When ischemia was
prolonged to 70 min after pretreatment with HOE642, infarct
size, recovery of systolic shortening, myocardial contracture,
and increase in heart rate did not differ from those of the
control group. Pretreatment with HOE642 increased the tolerance
to ischemia/reperfusion by approximately 20-25 min. Inhibition
of Na+/H+ exchange appears to be very promising in the clinical
treatment of acute myocardial ischemia and reperfusion.
PMID: 9269952 [PubMed - indexed for MEDLINE]
-
Infarct size limitation by a new Na(+)-H+ exchange inhibitor,
Hoe 642: difference from preconditioning in the role of protein
kinase C.
Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K.
Second Department of Internal Medicine, Sapporo Medical University
School of Medicine, Japan. miura@sapmed.ac.jp
OBJECTIVES: This study examined the effect of a new specific
Na(+)-H+ exchange inhibitor, Hoe 642, on infarct size and the
protective role of protein kinase C (PKC) by this agent. In
addition, we assessed the possible alteration of Hoe 642-induced
cardioprotection by commonly used animal anesthetic drugs. BACKGROUND:
Earlier studies on the contribution of Na(+)-H+ exchange to
ischemic injury were complicated by nonspecific actions of the
Na(+)-H+ exchange inhibitors, and the role of this exchanger
in myocardial infarction in vivo remains unclear. The difference
in anesthetic agents used in experiments could have resulted
in discrepant findings regarding cardioprotection of some interventions,
such as preconditioning and adenosine triphosphate-sensitive
potassium channel openers. METHODS: Infarction was induced by
30 min of coronary occlusion and 3 h of reperfusion in the rabbit
heart. In the first series of experiments, rabbits were anesthetized
with pentobarbital or ketamine/xylazine. Hoe 642 was injected
intravenously 10 min before ischemia or 5 min before reperfusion.
In the second series of experiments, rabbits received 25 mg/kg
body weight of polymyxin B (polyB), Hoe 642 plus polyB, preconditioning
with 5 min of ischemia and 5 min of reperfusion plus polyB or
preconditioning alone before 30 min of ischemia. RESULTS: In
pentobarbital-anesthetized rabbits, 0.3 mg/kg and 0.6 mg/kg
of Hoe 642 given before ischemia limited infarct size (as percent
area at risk [%IS/AR]) to 42.7 +/- 4.4% (SEM) and 26.2 +/- 5.4%,
respectively, from the control value of 55.1 +/- 3.5%. However,
injection of Hoe 642 before reperfusion did not change infarct
size (%IS/AR 49.6 +/- 4.9%, p = 0.387; power 0.81 for detecting
50% reduction). Infarct size limitation by the preischemic treatment
with Hoe 642 was similarly observed in the rabbits anesthetized
with ketamine/xylazine. In the polyB-treated rabbits, 0.6 mg/kg
of Hoe 642 significantly limited infarct size (%IS/AR was 28.3
+/- 3.8% with Hoe 642 and 50.1 +/- 7.5% without Hoe 642), although
preconditioning was blocked by the same dose of polyB (%IS/AR
was 39.3 +/- 6.1% with polyB and 11.3 +/- 2.4% without polyB).
CONCLUSIONS: Hoe 642 enhanced myocardial tolerance against infarction,
and this enhanced tolerance was not influenced by anesthetic
agents commonly used for infarct size studies. Infarct size
limitation by Hoe 642 was not inhibited by polyB, suggesting
that cardioprotection by Na(+)-H+ exchange inhibition is not
PKC mediated and thus may be unrelated to preconditioning.
PMID: 9060913 [PubMed - indexed for MEDLINE]
-
Dose-dependent reduction of myocardial infarct mass in rabbits
by the NHE-1 inhibitor cariporide (HOE 642).
Linz W, Albus U, Crause P, Jung W, Weichert A, Scholkens
BA, Scholz W.
Hoechst Marion Roussel, DG Cardiovascular Research, Frankfurt/Main,
Germany. wolfgang.linz@hmrag.com
The aim of this study was to investigate the dose-dependent
effect of pretreatment with the selective sodium-hydrogen exchange
NHE-subtype 1 inhibitor cariporide on myocardial infarct mass
in a rabbit model of coronary ligation and reperfusion. Furthermore,
in a second part of the study, we tested the effect of cariporide
in the rabbits when given prior to reperfusion. Rabbits (n=49)
were randomized in 7 groups: saline vehicle, cariporide: 0.01,
0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion
of a branch of the left coronary artery followed by 2 h reperfusion.
Cariporide was given as a bolus intravenously 10 min before
occlusion or 5 min before reperfusion. After reperfusion, myocardial
infarct mass was determined by triphenyl tetrazolium chloride
staining and expressed as a percent of area at risk. Cariporide
given intravenously 10 min before occlusion in doses of 0.01,
0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct
mass from 58+/-6% in controls to 48+/-4% (-17%, NS), 36+/-5%
(-38%, p<0.05), 26+/-6% (-55%, p<0.05), 11+/-4% (-81%,
p<0.05) respectively, whereas area at risk did not differ
in between the groups. The effect of the lowest dose of 0.01
mg/kg did not reach significance.Plasma levels at different
doses of cariporide were correlated to the respective infarct
mass. After coronary occlusion left ventricular end-diastolic
pressure (LVEDP) significantly increased throughout occlusion
and reperfusion. Cariporide in the doses of 0.3, 0.1 and 0.03
mg/kg normalized LVEDP when measured after 2 h reperfusion.
In controls hemodynamic parameters such as mean arterial blood
pressure (MAP), heart rate (HR), left ventricular pressure (LVP)
and LV dP/dt(max) were not significantly changed by ischemia/reperfusion
with the exception of MAP, LVP and LV dP/dt(max) which were
significantly decreased after 120 min reperfusion. Cariporide
at doses of 0.1, 0.03 and 0.01 mg/kg did not significantly influence
these parameters, whereas the highest dose of 0.3 mg/kg prevented
the decrease of MAP and LVP. Cariporide (0.3 mg/kg i.v.) administered
5 min before reperfusion significantly reduced infarct mass
by 31%. Under these conditions the increase of LVEDP after coronary
occlusion was not influenced by cariporide. As in the pretreatment
experiments, the decrease of MAP and LVP was prevented when
measured 2 h after reperfusion. The results show that pretreatment
with the NHE-subtype 1 inhibitor cariporide is cardioprotective
by reducing infarct mass in rabbits in a dose-dependent manner.
While the cardioprotective effect of pretreatment could be demonstrated
over a broad range of doses, the efficacy of the compound when
given only on reperfusion was significant but more limited.
PMID: 9764718 [PubMed - indexed for MEDLINE]
-
Time-dependent protection by Na+/H+ exchange inhibition in
a regionally ischemic, reperfused porcine heart preparation
with low residual blood flow.
Klein HH, Bohle RM, Pich S, Lindert-Heimberg S, Wollenweber
J, Schade-Brittinger C, Nebendahl K.
Med. Klinik II, Stadt. Krankenanstalten Idar-Oberstein GmbH,
Germany.
Inhibition of Na+/H+ exchange has been shown to protect the
ischemic reperfused myocardium. This study investigated the
time-dependent beneficial effect of the Na+/H+ exchange inhibitor
HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanedine methanesulphonite,
cariporide). The left anterior descending coronary artery was
ligated in 21 pigs (seven control animals) for 60 min and then
reperfused for 24 h. An extracorporeal bypass system was used
to achieve a constant residual blood flow of 3 ml/min within
the ischemic myocardium. Cariporide (1 mg/kg) was injected intravenously
in seven pigs after 15 min of ischemia (group A), and in another
seven animals after 45 min of ischemia (group B). Histochemical
(tetrazolium stain) and histologic infarct sizes were determined
at the end of the experiments. Regional systolic shortening
was determined by sonomicrometry. Mean calculated residual blood
flows (ml/min/g of ischemic myocardium) amounted to 0.106 (group
A), 0.093 (group B), and 0.117 (control group). Histochemical
(32.9 +/- 21%) and histologic infarct sizes (36.7 +/- 17.7%)
were significantly reduced in group A compared to both the control
group (histochemical infarct size, 62.5 +/- 16.1%, P < 0.01;
histologic infarct size. 67.8 +/- 16.3%, P = 0.013) and group
B (histochemical infarct size 64.8 +/- 12.2%, P < 0.01; histologic
infarct size 67.1 +/- 15.6%, P < 0.01). Infarct sizes of
group B did not differ from control values. Recovery of regional
systolic shortening after 24 h of reperfusion was insignificantly
improved in group A compared to both other groups. In conclusion,
inhibition of Na+/H+ exchange during early ischemia reduced
cell death in an ischemic reperfused preparation with low residual
blood flow.
PMID: 9602428 [PubMed - indexed for MEDLINE]
-
A rapid ischemia-induced apoptosis in isolated rat hearts
and its attenuation by the sodium-hydrogen exchange inhibitor
HOE 642 (cariporide).
Chakrabarti S, Hoque AN, Karmazyn M.
Departments of Pharmacology and Toxicology and Pathology, University
of Western Ontario, London, Ontario, N6A 5C1, Canada.
Apoptosis is a potentially important myocardial response to
pathology including ischemia and reperfusion. Na-H exchange
(NHE) represents an important mechanism for mediating such injury.
The present study was done to determine if NHE inhibition can
affect early apoptosis in an acute model of ischemia and reperfusion.
Isolated rat hearts were subjected to zero-flow ischemia for
various durations with or without subsequent 30 min of reperfusion.
Nick-end-labelling of biotin-dUTP (TUNEL staining), as well
as DNA extraction followed by agarose gel electrophoresis, were
used to semiquantify apoptotic cells and identify DNA laddering,
respectively. Apoptosis first appeared after 10 min of ischemia
and reached a maximum level after 30 min. The number of apoptotic
cells after 30 min of ischemia was 31 +/- 3 per 100 high power
microscopic fields, whereas in reperfused hearts the number
of cells was 34 +/- 3. To determine the effect of NHE inhibition,
hearts were pretreated 15 min prior to ischemia with HOE 642,
a potent and specific inhibitor of the isoform (NHE-1) found
in myocardium. HOE 642 significantly reduced the number of apoptotic
cells in the ischemic and reperfused heart to 2 +/- 1 and 6
+/- 1, respectively (P<0.05 from untreated hearts). DNA laddering
was not observed with electrophoretic DNA analysis, likely owing
to the small number of apoptotic cells involved. Hearts recovered
nearly 100% of function in both groups, although there was a
significantly higher recovery after 1 and 2 min of reperfusion
in those hearts treated with HOE 642. Our study shows that apoptosis,
albeit very mild in nature, can be rapidly induced in isolated
hearts by a relatively brief period of ischemia without reperfusion,
which can be markedly attenuated by the NHE inhibitor HOE 642.
The ability of HOE 642 to markedly attenuate apoptosis may be
important in terms of understanding the drug's cardioprotective
properties as well as the overall role of NHE in heart disease.
Copyright 1997 Academic Press Limited.
PMID: 9405190 [PubMed - indexed for MEDLINE]
-
-
Inhibition of the sodium-hydrogen exchanger with cariporide
to prevent myocardial infarction in high-risk ischemic situations.
Main results of the GUARDIAN trial. Guard during ischemia against
necrosis (GUARDIAN) Investigators.
Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T,
Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A.
BACKGROUND: The transmembrane sodium/hydrogen exchanger maintains
myocardial cell pH integrity during myocardial ischemia but
paradoxically may precipitate cell necrosis. The development
of cariporide, a potent and specific inhibitor of the exchanger,
prompted this investigation of the potential of the drug to
prevent myocardial cell necrosis. METHODS AND RESULTS: A total
of 11 590 patients with unstable angina or non-ST-elevation
myocardial infarction (MI) or undergoing high-risk percutaneous
or surgical revascularization were randomized to receive placebo
or 1 of 3 doses of cariporide for the period of risk. The trial
failed to document benefit of cariporide over placebo on the
primary end point of death or MI assessed after 36 days. Doses
of 20 and 80 mg every 8 hours had no effect, whereas a dose
of 120 mg was associated with a 10% risk reduction (98% CI 5.5%
to 23.4%, P=0.12). With this dose, benefit was limited to patients
undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to
41.5%, P=0.03) and was maintained after 6 months. No effect
was seen on mortality. The rate of Q-wave MI was reduced by
32% across all entry diagnostic groups (2.6% versus 1.8%, P=0.03),
but the rate of non-Q-wave MI was reduced only in patients undergoing
surgery (7.1% versus 3.8%, P=0.005). There were no increases
in clinically serious adverse events. CONCLUSIONS: No significant
benefit of cariporide could be demonstrated across a wide range
of clinical situations of risk. The trial documented safety
of the drug and suggested that a high degree of inhibition of
the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.
Publication Types:
|
Clinical trial
|
|
Randomized controlled trial |
PMID: 11120691 [PubMed - indexed for MEDLINE]
-
Protection against infarction afforded by preconditioning
is mediated by A1 adenosine receptors in rabbit heart.
Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA,
Downey JM.
Department of Medical Physiology, University of South Alabama,
Mobile 36688.
BACKGROUND. Preconditioning (5 minutes of ischemia followed
by 10 minutes of recovery) renders the heart very resistant
to infarction from subsequent ischemia. This study tests whether
adenosine receptors might mediate preconditioning protection.
METHODS AND RESULTS. We examined the effect on infarct size
of pretreatment with either of two adenosine receptor antagonists
in both control and preconditioned in situ rabbit hearts. Hearts
underwent 30 minutes of regional ischemia plus 3 hours of reperfusion,
and infarct size was measured with tetrazolium. Infarct size
averaged 39% of the zone at risk in controls but only 8% in
preconditioned hearts. Preconditioned and nonpreconditioned
hearts receiving either blocker had infarcts not different in
size from the controls. A 5-minute intracoronary infusion of
adenosine was as effective as 5 minutes of ischemia in protecting
parabiotically perfused isolated hearts against infarction from
a 45-minute ischemic insult. Similarly, intracoronary infusion
of N6-1-(phenyl-2R-isopropyl)adenosine, an A1-selective adenosine
receptor agonist, at a dose that delayed conduction but did
not dilate the coronary vessels, also limited infarct size.
The protection disappeared when we reduced the coronary concentration
of drug by intravenous infusion of adenosine, indicating that
cardiac rather than peripheral receptors were involved in the
protection. CONCLUSIONS. We conclude that adenosine released
during the preconditioning occlusion stimulates cardiac A1 receptors,
which leaves the heart protected against infarction even after
the adenosine has been withdrawn.
PMID: 2060105 [PubMed - indexed for MEDLINE]
-
Adenosine infusion during early reperfusion failed to limit
myocardial infarct size in a collateral deficient species.
Goto M, Miura T, Iliodoromitis EK, O'Leary EL, Ishimoto R,
Yellon DM, Iimura O.
Second Department of Internal Medicine, Sapporo Medical College,
Japan.
STUDY OBJECTIVE--Intracoronary or intravenous adenosine during
reperfusion in combination with lignocaine may attenuate "reperfusion
injury" and limit myocardial infarct size in the canine
heart. The aim of this study was to test whether intravenous
adenosine also protects myocardium in the rabbit heart, which
lacks xanthine oxidase and significant coronary collaterals
in contrast to the canine heart. DESIGN--Five groups of rabbits
underwent a 30 min occlusion of the circumflex coronary artery,
followed by reperfusion. In adenosine treated groups, either
a high dose of adenosine (0.37 mg.kg-1.min-1) with lignocaine
treatment (5 mg intravenously 1 min before coronary occlusion
and before reperfusion) or a low dose (0.15 mg.kg-1.min-1) of
adenosine with or without lignocaine was infused for 60 min
starting 5 min before the onset of reperfusion. Group 1 was
untreated, while group 2 received a high dose of adenosine with
lignocaine. These groups were reperfused for 3 h. Group 3 was
untreated, group 4 received a low dose of adenosine, and group
5 a low dose of adenosine and lignocaine. These groups were
reperfused for 72 h. EXPERIMENTAL MATERIAL--60 anaesthetised
open chest rabbits were used. Groups 1 and 2 were killed after
3 h coronary reperfusion. Groups 3, 4, and 5 recovered from
surgery for 72 h and were then killed for further study. MEASUREMENTS
AND MAIN RESULTS--The high dose of adenosine reduced mean blood
pressure to 44% of baseline value and diminished reactive hyperaemia
in the area at risk by "coronary steal". The low dose
of adenosine did not significantly alter systemic blood pressure
or heart rate. Infarct size did not differ between groups 1
and 2, at 39.7(SD 20.1)% of area at risk v 33.2(15.9)% (by tetrazolium
staining), nor between groups 3, 4, and 5: 50.3(12.6)% v 52.7(15.6)%
v 47.8(9.3)% (by histology). CONCLUSION--Neither a high dose
nor a low dose of adenosine limited myocardial infarct size
in the rabbit heart even when adenosine was combined with lignocaine
treatment.
PMID: 1813123 [PubMed - indexed for MEDLINE]
-
-
Comment in:
|
Circulation. 1992 Feb;85(2):845-7 |
Intravenous pretreatment with A1-selective adenosine analogues
protects the heart against infarction.
Thornton JD, Liu GS, Olsson RA, Downey JM.
Department of Physiology, University of South Alabama, Mobile
36688.
BACKGROUND. Recent data from this laboratory indicate that pretreatment
with adenosine can protect the heart against infarction via
A1-receptors, but because of systemic hypotension, adenosine
had to be given into the coronary circulation. METHODS AND RESULTS.
In this study, we tested whether the protection could be achieved
by intravenous administration of the A1-selective adenosine
agonists N6-(phenyl-2R-isopropyl)-adenosine (PIA) and 2-chloro-N6-cyclopentyladenosine
(CCPA). Nine groups of open-chest anesthetized rabbits were
subjected to 30 minutes of regional coronary ischemia and 3
hours of reperfusion. Infarct size was determined by tetrazolium
staining. Control hearts receiving no treatment had 38 +/- 4%
of the risk zone infarcted. Preconditioning with 5 minutes of
ischemia and 10 minutes of reperfusion before ischemia limited
the infarct to 8 +/- 4%. Intravenous PIA 15 minutes before 30-minute
ischemia also limited infarct size to 6 +/- 2% at the highest
dose. CCPA offered similar protection. When the PIA was given
at reperfusion, infarct size was 46 +/- 6%, indicating that
receptor activation must precede ischemia to protect. Pretreatment
with CGS 21680, a selective A2-receptor agonist, caused identical
hypotension but failed to limit infarct size (43 +/- 3%), indicating
again that the A1-receptor is involved. When rabbits pretreated
with PIA were paced at 220 beats per minutes, PIA still limited
infarct size (16 +/- 4%), indicating that protection was not
the result of bradycardia. CONCLUSIONS. These results indicate
that stimulation of adenosine A1-receptors causes the heart
to become resistant to ischemia and that this protection can
be achieved with intravenous administration of A1-selective
agents.
PMID: 1735160 [PubMed - indexed for MEDLINE]
-
-
Comment in:
|
Cardiovasc Res. 1997 Feb;33(2):497-500 |
Effect of adenosine therapy at reperfusion on myocardial
infarct size in dogs.
Vander Heide RS, Reimer KA.
Department of Pathology, Duke University Medical Center, Durham,
NC 27710, USA.
OBJECTIVES: The concept of lethal reperfusion injury in ischemic
myocardium has been the subject of controversy. Adenosine administered
during reperfusion has been reported to limit lethal reperfusion
injury in several studies. On the contrary, it has been reported
that cardioprotection may not be achieved with adenosine alone
but may occur if adenosine is co-administered with lidocaine.
Still other investigators have reported no beneficial effect
of adenosine, given with or without lidocaine. If the positive
reports are reproducible, they are important both because they
provide evidence for the existence of reperfusion injury and
establish a rationale for preventing it. Thus, the present study
was done to determine if adenosine could limit lethal reperfusion
injury in a canine model of regional myocardial ischemia and
reperfusion, carefully controlled for baseline predictors of
infarct size. METHODS: Dogs (n = 37) of either sex were subjected
to 90 min of coronary occlusion followed by 3 h of reperfusion.
Two groups of dogs received adenosine (150 micrograms/kg/min)
intravenously for 155 min starting 5 min prior to the reperfusion.
One treated group received adenosine only and a second group
received adenosine plus lidocaine (2 mg/kg). Control dogs received
a saline infusion. After 3 h of reflow, hearts were excised
and infarct size was measured and expressed as a percentage
of the ischemic area at risk (AAR). To control for variation
in infarct size due to variation in collateral blood flow (CBF),
infarct size among groups was compared using ANCOVA, using CBF
as the independent variable and infarct size as the dependent
variable. RESULTS: Transmural collateral blood flow and AAR
were not significantly different between any of the groups.
Mean infarct size (adjusted by ANCOVA) in control dogs (n =
9) was 38.1 +/- 5.3% of the AAR. Neither adenosine (n = 9) nor
adenosine plus lidocaine (n = 7) significantly limited infarct
size (35.6 +/- 5.6% AAR and 38.1 +/- 7.7% AAR, respectively;
both P = NS). CONCLUSIONS: Intravenous adenosine therapy (150
micrograms/kg/min) during reperfusion, whether administered
alone or in dogs previously treated with lidocaine, did not
limit infarct size after 90 min of regional ischemia in canine
myocardium.
PMID: 8763400 [PubMed - indexed for MEDLINE]
-
Reduction of reperfusion injury in the canine preparation
by intracoronary adenosine: importance of the endothelium and
the no-reflow phenomenon.
Olafsson B, Forman MB, Puett DW, Pou A, Cates CU, Friesinger
GC, Virmani R.
Department of Medicine, Vanderbilt University Medical Center,
Nashville, TN 37232.
We hypothesized that the endogenous coronary vasodilator adenosine
may reduce infarct size by progressively increasing reflow in
a preparation of coronary occlusion-reperfusion. After 90 min
of proximal left anterior descending artery occlusion, 20 dogs
were randomized to blood reperfusion with (n = 10) or without
(n = 10) adenosine into the proximal left anterior descending
vessel at 3.75 mg/min for 60 min after reperfusion. Regional
myocardial blood flow was determined serially with microspheres
and regional ventricular function was assessed by a computerized
radial shortening method. At 24 hr, the area at risk was defined
in vivo with monastral blue dye and area of necrosis was determined
after incubation of left ventricular slices in triphenyltetrazolium
chloride. Hemodynamic variables were similar in the two groups
during the experimental protocol. Infarct size was significantly
reduced in treated animals, both when expressed as a percentage
of the area at risk (9.9 +/- 2.8% vs 40.9 +/- 6.6%, p less than
.001) and as a percentage of the left ventricle (4.6 +/- 1.3%
vs 18.0 +/- 3.4%, p = .002). This was associated with significant
improvement in radial shortening in the ischemic zone 24 hr
after reperfusion (10.1 +/- 2.5 vs -2.8 +/- 2.2%, p less than
.01). Regional myocardial blood flow was significantly increased
in endocardial and epicardial regions from the lateral ischemic
zone 1 hr after reperfusion in adenosine-treated animals. Light
microscopy demonstrated decreased neutrophil infiltration in
the ischemic zone and electron microscopy showed relative preservation
of endothelial structure in the subendocardium with reduced
neutrophil and red cell stagnation of capillaries in the treated
group. These findings suggest that intracoronary administration
of adenosine after reperfusion significantly reduces infarct
size and improves regional ventricular function in the ischemic
zone in the canine preparation.
PMID: 3664998 [PubMed - indexed for MEDLINE]
-
Reduction of myocardial reperfusion injury by intravenous
adenosine administered during the early reperfusion period.
Pitarys CJ 2nd, Virmani R, Vildibill HD Jr, Jackson EK, Forman
MB.
Department of Medicine, Vanderbilt University School of Medicine,
Nashville, Tenn.
Adenosine influences the function of several cell types thought
to be involved in the pathogenesis of myocardial reperfusion
injury. We have previously demonstrated that intracoronary administration
of adenosine enhances myocardial salvage 24 hours after reperfusion.
To determine if these beneficial effects could be obtained during
a prolonged period of reperfusion using an intravenous route
of administration, 22 closed-chest dogs were subjected to 90
minutes of proximal left anterior descending coronary artery
occlusion and 72 hours of reperfusion. Animals randomly received
either intravenous adenosine (0.15 mg/kg/min) or an equal volume
of Ringer's lactate during the first 150 minutes of reperfusion.
The area at risk was defined in vivo with Monastral blue, and
infarct size was measured histologically with Mallory's trichrome
stain. Serial global and regional ventricular function were
determined with contrast ventriculography and analyzed using
a computerized radial shortening method. Biopsies were obtained
from the central ischemic zone to assess endothelial ultrastructure
and capillary obstruction. No significant effects in heart rate
or blood pressure were noted during adenosine infusion. Transmural
collateral blood flow during ischemia was similar in the groups.
Infarct size expressed as a percentage of the anatomical area
at risk was significantly less in the adenosine-treated group
(35.3 +/- 4.3% in controls versus 17.1 +/- 4.3% in treated animals,
p less than 0.01). A progressive decrease in transmural blood
flow was noted in control animals during reperfusion, resulting
in a significant reduction at 3 hours compared with the preocclusion
value (0.69 +/- 0.11 ml/min/g [at baseline versus 0.45 +/- 0.10
ml/min/g at 3 hours, p less than 0.05]). In contrast, flow in
adenosine animals at 3 hours was similar to baseline values
(0.91 +/- 0.15 ml/min/g at baseline versus 0.98 +/- 0.14 ml/min/g
at 3 hours, p = NS) and was significantly higher (p less than
0.05) than the control group. Radial shortening in the ischemic
zone was significantly improved at 3 (-2.6 +/- 2.8% in controls
versus 11.6 +/- 3.3% in treated animals, p less than 0.01) and
72 hours (5.5 +/- 2.0% in controls versus 17.3 +/- 3.5% in treated
animals, p less than 0.01) after reperfusion in treated animals.
Electron microscopy showed reduced neutrophil and erythrocyte
plugging of capillaries with relative preservation of endothelial
cell structure in the adenosine group.(ABSTRACT TRUNCATED AT
400 WORDS)
PMID: 1984882 [PubMed - indexed for MEDLINE]
-
Administration of adenosine during reperfusion reduces injury
of vascular endothelium and death of myocytes.
Zhao ZQ, Nakamura M, Wang NP, Wilcox JN, Shearer S, Guyton
RA, Vinten-Johansen J.
Department of Cardiothoracic Surgery, Emory University School
of Medicine, Atlanta, Georgia 30365-2225, USA.
INTRODUCTION: To test the hypothesis that administration of
adenosine during reperfusion attenuates endothelial dysfunction
and extension of infarct size by inhibiting polymorphonuclear
neutrophil (PMN)-mediated events and apoptosis. METHODS: Anesthetized
dogs were subjected to 1 h coronary artery occlusion and 6 h
of reperfusion with infusion of saline (vehicle, n = 8) or 140
micrograms/kg per min adenosine, n = 8) continuously into the
left atrium starting 5 min before reperfusion and continuing
for 2 h. RESULTS: There was no intergroup difference in collateral
myocardial blood flow measured by using colored microspheres
in the area at risk during ischemia. Infusion of adenosine transiently
improved segmental shortening (4.1 +/- 3.1% versus -2.5 +/-
2.3%, P < 0.05) and segmental work (41.4 +/- 22 versus 15
+/- 13 mmHg/mm, P < 0.05) after 4 h of reperfusion. Infusion
of adenosine reduced size of infarct (determined by staining
with triphenyltetrazolium chloride) from 27 +/- 2% with vehicle
to 14 +/- 1%, (P < 0.05). This was confirmed by measuring
that it lowered activity of plasma creatine kinase (from 19
+/- 2 versus 8 +/- 1 IU/g protein, P < 0.05). It also reduced
the proportion of terminal deoxynucleotidyl transferase-mediated
dUTP nick-end labeling-positive nuclei in the perinecrotic zone
from 17.3 +/- 1.6 to 10.3 +/- 1.0% (P < 0.05) and reduced
the appearance of DNA ladders in gel electrophoresis. In addition,
it significantly decreased accumulation of PMN in the ischemic
area (determined by immunohistochemistry with anti-CD18 antibody)
and activity of cardiac myeloperoxidase compared with vehicle
(439 +/- 52 versus 183 +/- 20 PMN/mm2 myocardium and 1.1 +/-
0.1 versus 2.4 +/- 0.2 U/100 mg tissue, P < 0.05, respectively).
Furthermore, infusion of adenosine during reperfusion preserved
vascular endothelial function expressed in terms of a decrease
in adherence of PMN to postischemic coronary artery endothelium
(63 +/- 3 versus 36 +/- 4 PMN/mm2 endothelium, P < 0.05,
basal function) and agonist (acetylcholine)-induced endothelium-dependent
relaxation (negative logarithm to base 10 of concentration (mol/l)
for half-maximal effect 7.7 +/- 0.1 versus 7.2 +/- 0.1, P <
0.05, stimulated function). Infusion of adenosine directly inhibited
generation of superoxide radical from canine PMN in vitro dose
dependently from 27.8 +/- 6.3 to 5.8 +/- 2.1 nmol/l/5 x 10(6)
PMN (P < 0.05). CONCLUSION: Intra-atrial infusion of adenosine
during reperfusion reduced accumulation of PMN in area at risk,
preserved vascular endothelial function after ischemia-reperfusion
by inhibiting interaction between PMN and endothelial cells,
and decreased extension of infarct, possibly by limiting apoptosis.
PMID: 10599541 [PubMed - indexed for MEDLINE]
-
-
Adenosine as an adjunct to thrombolytic therapy for acute
myocardial infarction: results of a multicenter, randomized,
placebo-controlled trial: the Acute Myocardial Infarction STudy
of ADenosine (AMISTAD) trial.
Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar
MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte
V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB.
Duke Clinical Research Institute, Durham, North Carolina 27715,
USA. mahaf002@mc.duke.edu
OBJECTIVES: The Acute Myocardial Infarction STudy of ADenosine
(AMISTAD) trial was designed to test the hypothesis that adenosine
as an adjunct to thrombolysis would reduce myocardial infarct
size. BACKGROUND: Reperfusion therapy for acute myocardial infarction
(MI) has been shown to reduce mortality, but reperfusion itself
also may have deleterious effects. METHODS: The AMISTAD trial
was a prospective, open-label trial of thrombolysis with randomization
to adenosine or placebo in 236 patients within 6 h of infarction
onset. The primary end point was infarct size as determined
by Tc-99 m sestamibi single-photon emission computed tomography
(SPECT) imaging 6+/-1 days after enrollment based on multivariable
regression modeling to adjust for covariates. Secondary end
points were myocardial salvage index and a composite of in-hospital
clinical outcomes (death, reinfarction, shock, congestive heart
failure or stroke). RESULTS: In all, 236 patients were enrolled.
Final infarct size was assessed in 197 (83%) patients. There
was a 33% relative reduction in infarct size (p = 0.03) with
adenosine. There was a 67% relative reduction in infarct size
in patients with anterior infarction (15% in the adenosine group
vs. 45.5% in the placebo group) but no reduction in patients
with infarcts located elsewhere (11.5% for both groups). Patients
randomized to adenosine tended to reach the composite clinical
end point more often than those assigned to placebo (22% vs.
16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89).
CONCLUSIONS: Many agents thought to attenuate reperfusion injury
have been unsuccessful in clinical investigation. In this study,
adenosine resulted in a significant reduction in infarct size.
These data support the need for a large clinical outcome trial.
Publication Types:
|
Clinical trial
|
|
Multicenter study
|
|
Randomized controlled trial |
PMID: 10577561 [PubMed - indexed for MEDLINE]
|
