Vol. 280, Issue 5, H2406-H2411, May 2001
RAPID COMMUNICATION
Chemical preconditioning with 3-nitropropionic acid in hearts:
role of mitochondrial KATP channel
Ramzi A.
Ockaili,
Peeyush
Bhargava, and
Rakesh C.
Kukreja
Division of Cardiology, Department of Medicine, Medical College of
Virginia, Virginia Commonwealth University, Richmond, Virginia
23298
 |
ABSTRACT |
We investigated the
cardioprotective effect of 3-nitropropionic acid (3-NPA), an inhibitior
of mitochondrial succinate dehydrogenase, and we wanted to show whether
this protection is mediated by of opening mitochondrial ATP-sensitive
potassium (KATP) channels. Adult rabbits were treated with
either 3-NPA (3 mg/kg iv) or saline (n = 6 rabbits/group). After 30 min (for early phase) or 24 h (for late
phase) of the treatment, the animals were subjected to 30 min of
ischemia and 3 h of reperfusion
(ischemia-reperfusion). 5-Hydroxydecanoate (5-HD, 5 mg/kg
iv),the mitochondrial KATP channel blocker, was
administered 10 min before ischemia-reperfusion in the saline-
and 3-NPA-treated rabbits. 3-NPA caused a decrease in the infarct size
from 27.8 ± 4.2% in the saline group to 16.5 ± 1.0% in
the 3-NPA-treated rabbits during early phase and from 30.4 ± 4.2% in the saline group to 17.6 ± 1.05 in the 3-NPA group during delayed phase (P < 0.05, % of risk
area). The anti-infarct effect of 3-NPA was blocked by 5-HD as
shown by an increase in infarct size to 33 ± 2.7% (early phase)
and 31 ± 2.4% (delayed phase) (P < 0.05 vs.
3-NPA groups). 5-HD had no proischemic effect in
control animals. Also, 3-NPA had no effect on systemic hemodynamics. We
conclude that 3-NPA induces long-lasting anti-ischemic effects via opening of mitochondrial KATP channels.
ischemia; succinate dehydrogenase; oxidative
phosphorylation
| |
INTRODUCTION |
ISCHEMIC
PRECONDITIONING is a phenomenon whereby brief episode(s) of
sublethal ischemia protect the heart against sustained ischemia-reperfusion injury (22). Considerable
progress has been made toward identifying cellular triggers and signal
transduction mechanisms that may be involved in the process of
preconditioning. A number of receptors and intracellular signaling
pathways have been identified as being integral components of the
cardioprotective effect of preconditioning (12).
Endogenously released agents involved in preconditioning include
adenosine (18), norepinephrine (5), opioids
(28), and free radicals (nitric oxide/superoxide/hydrogen peroxide) (9, 32). In addition, a number of
pharmacological agents such as the nontoxic derivative of endotoxin
monophosphoryl lipid A or its synthetic derivative RC-552
(36-39), as well as openers of ATP-sensitive
potassium (KATP) channels (4, 24, 34), have
also been shown to induce a preconditioning-like effect in various
species. In the present study, we used a novel approach of
preconditioning the heart against ischemia-reperfusion injury by mild inhibition of oxidative phosphorylation with 3-nitropropionic acid (3-NPA). 3-NPA inhibits succinate dehydrogenase (SDH) activity by
covalent binding (11) and has been shown to decrease the level of ATP present in mouse cortical explants and hippocampal slices
(20, 27). Chemical preconditioning with 3-NPA has been shown to have a protective effect against ischemic hypoxic
neuronal damage in vitro (1, 25, 26) and in vivo
(31). However, no studies are available to show whether
3-NPA induces a preconditioning-like effect following
ischemia-reperfusion in the heart. Accordingly, one of the
major goals of this investigation was to show whether pretreatment with
3-NPA induces an early and delayed cardioprotective effect in vivo.
Because opening mitochondrial KATP channels has been
proposed as the end effectors of preconditioning (18), a
second goal of this study was to show whether the protective effect of
3-NPA is also dependent on the opening of this channel. Using an in
situ rabbit model of myocardial infarction, we demonstrated that this
drug induced both early and delayed cardioprotective effects, which
were blocked by the selective inhibitor of mitochondrial KATP channel 5-hydroxydecanoate (5-HD).
| |
MATERIALS AND METHODS |
Animals.
Male New Zealand White rabbits (2.8-3.3 kg) were used in these
studies. The rabbits were supplied by the Blue and Gray Rabbitry (Unionville Lane, Virginia). The animals were allowed to readjust to
the new housing environment for at least a week before the experiment.
The care and use of animals were conducted in accordance with the
guidelines of the Committee on Animals of Virginia Commonwealth University and the National Institutes of Health Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 80-23, Revised, Office of Science and Health Reports, Bethesda, MD
20205].
Drugs and Chemicals.
5-HD was purchased from Research Biochemicals International (Nalich,
MD). 3-NPA, Evans Blue dye, and triphenyltetrazolium chloride were
obtained from Sigma (St. Louis, MO).
Surgical preparation.
The animals were anesthetized with an intramuscular injection of
ketamine HCl (35 mg/kg) and xylazine (5 mg/kg). Additional injections
of the ketamine-xylazine mixture were given as needed throughout the
surgical procedure. All surgical procedures were performed under
sterile conditions. Arterial blood gases and pH were measured during
the experimental protocol to ensure proper physiological respiration
during the experiment. The chest was opened by a left thoracotomy in
the fourth intercostal space, and the pericardium was opened to expose
the heart. A 5-0 silk suture with an atraumatic needle was then passed
around the left anterior descending (LAD) artery. The snare was
pulled and then fixed in place with a hemostat, thus inducing regional
ischemia. Myocardial ischemia was confirmed visually in
situ by regional cyanosis, S-T segment elevation/depression, or T wave
inversion, hypokinetic movement of the myocardium, and relative
hypotension. The details of surgical procedures have been reported
previously (7).
Measurement of infarct size.
Risk area was demarcated by Evans blue, and infarct size was measured
using tetrazolium-stained sections (7). The area for each
region was determined by digital planimetry with computer morphometry
using a Bioquant imaging software. Infarct size was expressed both as a
percentage of the total left ventricle and as a percentage of the
ischemic risk area.
Measurement of hemodynamics.
Hemodynamic parameters heart rate, mean arterial blood pressure (MAP),
and rate-pressure product (RPP, the product of the heart rate and peak
arterial pressure) were continuously measured throughout the
experimental protocol using a strip-chart recorder.
Study protocol.
The rabbits were randomly assigned to one of the following groups. All
animals were subjected to 30 min of sustained ischemia followed
by 180 min of reperfusion. The effect of 3-NPA in the absence or
presence of 5-HD was studied in two phases; i.e., the early phase and
the delayed phase. In the early phase, a myocardial infarction protocol
was carried out 30 min after treatment with 3-NPA. In the late phase,
this protocol was carried out 24 h after 3-NPA treatment. The
following groups were studied (Fig.
1). In group I
(control, n = 6 ), rabbits received no treatment.
Group II (vehicle, n = 7) consisted of
rabbits receiving only saline. Seven rabbits were used in the early
phase (with infarction protocol followed 30 min after saline
injection), and eight were used in the delayed phase (with infarction
protocol carried out 24 h later, group IIa). In
group III (3-NPA, n = 12), animals were
chemically preconditioned with 3-NPA (3 mg/kg iv). Six rabbits were
used in the early phase, and six were used in the delayed phase (24 h,
group IIIa). Group IV (5-HD, n = 7) consisted of rabbits treated with 5-HD (5 mg/kg iv) 10 min before
sustained ischemia and reperfusion. Group V
(3-NPA + 5HD, n = 12 ) had 3-NPA-treated rabbits
given 5-HD 10 min before sustained ischemia and reperfusion.
Six rabbits were used in each of the early phase and delayed phase
(group Va) of 3-NPA treatment.
View larger version (15K):
[in this window]
[in a new window]
|
Fig. 1.
Experimental protocol showing the times of administration
of 3-nitropropionic acid (3-NPA)-saline and 5-hydrpxydecanoate (5-HD)
during early phase and late phase of chemical preconditioning. TTC,
triphenyltetrazolium chloride.
|
|
Statistics.
All measurements of infarct size and risk areas are expressed as group
means ± SE. Changes in hemodynamics and infarct size variables
were analyzed by ANOVA to determine the main effect of time, group, and
time by group interaction. If the global tests showed major
interactions, post hoc contrasts between different time points within
the same group or between different groups were performed using a
t-test. Statistical differences were considered significant
if P value was <0.05.
| |
RESULTS |
Exclusion and mortality.
A total of 78 rabbits were initially used in this study. Thirteen
animals had to be excluded because of the following reasons: ventricular arrhythmia during LAD occlusion, congestive heart failure
during the first 30 min of reperfusion, cardiogenic shock during
reperfusion, and technical problems in demarcating the risk area. A
total of 65 rabbits were used for data analysis.
Infarct size.
During the early phase, chemical preconditioning with 3-NPA resulted in
significant decrease in the infarct size from 27.8 ± 4.2% in the
saline group to 16.5 ± 1.0% in the 3-NPA-treated rabbits, a 41%
reduction compared with the saline-treated animals (means ± SE,
P < 0.01, Fig.
2A). The infarct size
increased significantly to 32.99 ± 2.66%
(P < 0.05) when 5-HD was given 10 min before ischemic-reperfusion in the 3-NPA-treated rabbits. 5-HD alone had an infarct size of 33.5 ± 1.9%, which was not significantly different compared with the untreated (28.5 ± 1.8%) as well as the saline-treated rabbits (26.8 ± 3.45%) subjected to
ischemia-reperfusion protocol. Also, the infarct size was not
significantly different between the control and the vehicle-treated
rabbits (28.5 ± 1.8% vs. 27.8 ± 4.2%, P > 0.05). A similar trend in the changes in infarct size was
observed when expressed as a percentage of the left ventricle. The risk
areas expressed as a percentage of the left ventricle ranged from 45%
to 75% with no statistically significant difference between the groups
(P > 0.05). These data suggest that changes in the
infarct size observed among various groups were not related to the
percentage of the area of the left ventricle that was occluded by our
technique.
View larger version (24K):
[in this window]
[in a new window]
|
Fig. 2.
A: bar diagram showing infarct size during
early phase of cardioprotection with 3-NPA. Control, animals receiving
no treatment; vehicle, rabbits receiving saline, which was used for the
injection of 3-NPA. 3-NPA, animals pharmacologically preconditioned
with 3-NPA (3 mg/kg iv) 30 min before ischemia-reperfusion.
5-HD, control rabbits treated with 5-HD (5 mg/kg) 10 min before
sustained ischemia and reperfusion. 3-NPA + 5-HD,
3-NPA-treated rabbits given 5-HD (5 mg/kg iv) 10 min before sustained
ischemia and reperfusion. Results are means ± SE in
6-7 rabbits in each group. *P < 0.05 compared
with control, saline, 3-NPA + 5-HD and 5-HD groups. B:
infarct size during late phase of cardioprotection with 3-NPA.
Experimental groups were the same as in described in A
except that the animals were subjected to the infarction protocol
24 h following treatment with vehicle or 3-NPA. Results are
means ± SE in 6-7 rabbits in each group. *P < 0.05 compared with saline and 3-NPA + 5-HD groups.
|
|
During the late phase, the infarct size (% risk area) reduced
significantly from 30.4 ± 4.2% in the saline-treated rabbits to
17.6 ± 0.9% in the 3-NPA-treated group, which represented a 42%
decrease (P < 0.05, Fig. 2B). Again,
3-NPA-induced delayed protection was abolished by 5-HD as indicated by
increased infarct size (30.9 ± 2.4%, P < 0.05).
A similar trend was observed when infarct size was expressed as a
percentage of the left ventricle. Also, the risk area ranged from 44 to
70% with no significant differences among the groups.
Systemic hemodynamics.
The heart rate, MAP, and RPP during ischemia and reperfusion
for early and delayed phase are shown in Tables
1 and
2. There was no significant
difference in the baseline levels of these parameters between the
groups. Moreover, the heart rate, MAP, and RPP remained reasonably
stable throughout the reperfusion time period, although they decreased
gradually in all of the groups. Except at the indicated time points,
the mean values were not significantly different between the groups, as
well as at any time point within the groups.
| |
DISCUSSION |
The main goal of this investigation was to demonstrate whether
3-NPA, an inhibitor of SDH, induces an early and delayed
preconditioning-like effect following ischemia-reperfusion in
the rabbit heart. In addition, we wanted to understand whether opening
of mitochondrial KATP channels played an obligatory role in
3-NPA-induced ischemic protection in the heart. Our
results show that 3-NPA induced an immediate (early) and delayed
cardioprotective effect in the heart as indicated by a significant
decrease in the infarct size compared with the untreated control or
vehicle (saline)-treated animals. The selective blocker of
mitochondrial KATP channels 5-HD, when administered before
ischemia-reperfusion, abolished the early as well as the late
phase of cardioprotection induced by 3-NPA. No major differences in the
heart rate, MAP, or RPP were observed between the groups during the
infarction protocol, suggesting that the changes in myocardial infarcts
were independent of the systemic hemodynamics. Taken together, our
results suggest that 3-NPA induces long-lasting powerful
preconditioning-like effect in the heart, which is dependent on opening
of the mitochondrial KATP channel.
3-NPA is a toxin produced on moldy crops (sugarcane, peanuts, etc.) and
is known to cause severe neurological disorders in humans when consumed
in sufficient amounts (23). In vitro studies have shown
that 3-NPA irreversibly inactivates SDH, a Complex II respiratory
enzyme required for mitochondrial energy production (23).
3-NPA caused an immediate (1 h) and long-lasting (3 day) 30% reduction
in activity of SDH throughout the brain in vivo. Only a short metabolic
impairment occurred as indicated by a transient decrease in ATP (35%)
within 30 min followed by recovery within 2 h (35).
These studies demonstrated that 3-NPA can also induce profound
tolerance to focal cerebral ischemia in the rat when administered in a single dose (20 mg/kg) 3 days before
ischemia. The infarcts were ~70% and 35% smaller in the
3-NPA-preconditioned groups of permanent and transient focal cerebral
ischemia, respectively. Also, 3-NPA preconditioning neither
induced necrosis, apoptosis, or any other histologically
detectable damage to the brain, nor did it affect behavior of the
animals in these studies. However, no studies are available to show the
beneficial effect of 3-NPA during ischemia-reperfusion injury
in the heart. In the present study, we demonstrate that a much lower
dose of 3-NPA (3 mg/kg) is also able to chemically precondition the
heart against sustained ischemia induced either immediately
(within 30 min) or 24 h postdrug treatment. The degree of infarct
size reduction with 3-NPA was comparable to the one observed with
ischemic, heat shock, or pharmacological preconditioning
reported previously (8, 16, 39). We did not perform time
course of protection following 3-NPA treatment. Therefore, it is not
clear whether this protection was sustained or was similar to the
biphasic effect observed by ischemic preconditioning of the
heart (21). At this dose level (3 mg/kg), we did not observe a significant effect of 3-NPA on hemodynamics during
ischemia-reperfusion compared with the saline controls.
Our studies also showed that 3-NPA-induced protection was blocked by
5-HD, suggesting that the opening of mitochondrial KATP channels plays a crucial role in mediating the chemical
preconditioning. Recent studies have shown that opening the
mitochondrial KATP channel is one of the common mediators
of acute and delayed preconditioning induced by pathophysiological
stressors, including sublethal ischemia and heat shock
(7, 14, 15, 29), as well as pharmacological agents such as
adenosine, opioids, and endotoxin derivatives (3, 8, 13,
16). Thus in this respect, 3-NPA shares the same mechanistic
pathway, although the cellular signal transduction cascades leading to
the opening of mitochondrial KATP channels remain unknown.
von Arnim et al. (33) suggested that the early (onset
within hours) but not the late neuroprotection (within days) upon
chemical preconditioning with 3-NPA was associated with a selective
upregulation of adenosine A3 receptor mRNA. Other studies
have shown that 3-NPA (3 or 10 mg/kg) caused the activation of c-Jun
NH2-terminal kinase, which was linked with induced
tolerance to subsequent ischemia and prevention of delayed
neuronal death (30). However, activation of p38
mitogen-activate protein kinases or the extracellular signal-regulated
kinases were not detected by chemical preconditioning with 3-NPA in
these studies. Wiegand et al. (35) showed that
3-NPA induces a burst of reactive oxygen species, and the free radical
scavenger dimethylthiourea, when administered shortly before the 3-NPA
stimulus, completely blocked preconditioning. 3-NPA treatment has also
been associated with an elevated bcl-2:bax ratio (increased bcl-2
expression, decreased bax expression), both at the transcriptional
(mRNA) and the translational (protein) level, suggesting that the drug
may be protecting the ischemic brain injury by inhibiting
apoptosis (10). It is noteworthy that several of
the above-described mechanisms such as activation of adenosine receptor
subtypes (2, 17, 19), generation of oxygen-derived free
radicals (32), and elevation of bcl-2:bax ratio
(6) have been implicated in the mechanisms of early and late ischemic preconditioning of the heart. Further studies are required to understand whether 3-NPA also caused activation of similar
pathways in the heart.
In summary, the present study describes a novel strategy of producing
long-lasting protection of the heart against
ischemia-reperfusion injury by chemical preconditioning with
3-NPA. We have also shown that the protection induced by 3-NPA was
mediated by opening of mitochondrial KATP channels, a
fundamental mechanism of protection described previously for
preconditioning induced by pathophysiological stressors; e.g.,
sublethal ischemia-heat shock as well as a number of
pharmacological agents. Further studies are required to identify 3-NPA-triggered signaling mechanisms that lead to the opening of
mitochondrial KATP channel following 3-NPA induced early or delayed ischemic protection.
| |
ACKNOWLEDGEMENTS |
This work was supported in part by National Heart, Lung, and Blood
Institute Grants HL-51045 and HL-59469 (to R. C. Kukreja).
| |
FOOTNOTES |
Address for reprint requests and other correspondence: R. C. Kukreja, Box 281, Division of Cardiology, Medical College of Virginia,
Virginia Commonwealth Univ., Richmond, VA 23298 (E-mail: rakesh{at}hsc.vcu.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 13 December 2000; accepted in final form 31 January 2001.
| |
REFERENCES |
1.
Aketa, S,
Nakase H,
Kamada Y,
Hiramatsu KI,
and
Sakaki T.
Chemical preconditioning with 3-nitropropionic acid in gerbil hippocampal slices: therapeutic window and the participation of adenosine receptor.
Exp Neurol
166:
385-391,
2000[ISI][Medline].
2.
Armstrong, S,
and
Ganote CE.
Adenosine receptor specificity in preconditioning of isolated rabbit cardiomyocytes: evidence of A3 receptor involvement.
Cardiovasc Res
28:
1049-1056,
1994[Abstract/Free Full Text].
3.
Auchampach, JA,
and
Gross GJ.
Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs.
Am J Physiol Heart Circ Physiol
264:
H1327-H1336,
1993[Abstract/Free Full Text].
4.
Auchampach, JA,
Maruyama I,
Cavero I,
and
Gross GJ.
The new K+ channel opener aprikalim (RP52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes.
J Pharmacol Exp Ther
259:
961-967,
1989[Abstract/Free Full Text].
5.
Banerjee, A,
Locke-Winter CR,
Rogers KB,
Mitchell MB,
Brew EC,
Cairns CB,
Bensard DD,
and
Harken AH.
Preconditioning against myocardial dysfunction after ischemia and reperfusion by an 
1 adrenergic mechanism.
Circ Res
73:
656-670,
1993[Abstract/Free Full Text].
6.
Bernardo, NL,
Chelliah J,
D'Angelo M,
Shah MR,
Grant S,
and
Kukreja RC.
The second window of protection induces expression of protooncogene Bcl2 and inhibits apoptosis in rabbit heart (Abstract).
Circulation, Suppl
96:
I-553,
1997.
7.
Bernardo, NL,
D'Angelo M,
Okubo S,
Joy A,
and
Kukreja RC.
Second window of ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart.
Am J Physiol Heart Circ Physiol
276:
H1323-H1330,
1999[Abstract/Free Full Text].
8.
Bernardo, NL,
Okubo S,
Maaieh M,
Wood MA,
and
Kukreja RC.
Delayed preconditioning with adenosine is mediated by opening of ATP-sensitive K+ channels in the rabbit heart.
Am J Physiol Heart Circ Physiol
277:
H128-H135,
1999[Abstract/Free Full Text].
9.
Bolli, R,
Manchikalapudi S,
Tang XL,
Takano H,
Qiu Y,
Guo Y,
Zhang Q,
and
Jadoon AK.
The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning.
Circ Res
81:
1094-1107,
1997[Abstract/Free Full Text].
10.
Brambrink, TM,
Schneider T,
Noga H,
Astheimer A,
Gotz T,
Korner T,
Heimann A,
Welschof T,
and
Kempski O.
Tolerance-Inducing dose of 3-nitropropionic acid modulates bcl-2 and bax balance in the rat brain: a potential mechanism of chemical preconditioning.
J Cereb Blood Flow Metab
20:
1425-1436,
2000[ISI][Medline].
11.
Cole, CJ,
Edmondson DE,
and
Singer TP.
Inactivation of succinate dehydrogenase by 3-nitropropionate.
J Biol Chem
254:
5161-5167,
2000[Free Full Text].
12.
Downey, JM,
and
Cohen MV.
Signal transduction in ischemic preconditioning.
Adv Exp Med Biol
430:
39-55,
1997[ISI][Medline].
13.
Fryer, RM,
Hsu AK,
Eells JT,
Nagase H,
and
Gross GJ.
Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels.
Circ Res
84:
846-851,
2000[Abstract/Free Full Text].
14.
Gross, GJ,
and
Auchampach JA.
Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs.
Circ Res
70:
223-233,
1992[Abstract/Free Full Text].
15.
Hoag, JB,
Qian YZ,
Nayeem MA,
D'Angelo M,
and
Kukreja RC.
ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart.
Am J Physiol Heart Circ Physiol
273:
H861-H868,
1997[Abstract/Free Full Text].
16.
Janin, Y,
Qian YZ,
Hoag J,
Elliott GT,
and
Kukreja RC.
Pharmacologic preconditioning with monophosphoryl lipid A is abolished by 5-hydroxydecanoate, a specific inhibitor of the KATP channel.
J Cardiovasc Pharmacol
32:
337-342,
1998[ISI][Medline].
17.
Liu, GS,
Richards SC,
Olsson RA,
Mullane K,
Walsh RS,
and
Downey JM.
Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart.
Cardiovasc Res
28:
1057-1061,
1994[Abstract/Free Full Text].
18.
Liu, Y,
Sato T,
O'Rourke B,
and
Marban E.
Mitochondrial ATP-dependent potassium channels-novel effectors of cardioprotection?
Circulation
97:
2463-2469,
1998[Abstract/Free Full Text].
19.
Liu, GS,
Thornton J,
Van Winkle DM,
Stanley AWH,
Olsson RA,
and
Downey JM.
Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart.
Circulation
84:
350-356,
1991[Abstract/Free Full Text].
20.
Ludolph, AC,
Seelig M,
Ludolph A,
Novitt P,
Allen N,
Spencer PS,
and
Sabri MR.
3-Nitropropionic acid decreases cellular energy levels and causes neuronal degeneration in cortical implants.
Neurodegeneration
1:
155-161,
1992.
21.
Marber, MS,
Latchman DS,
Walker JM,
and
Yellon DM.
Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction.
Circulation
88:
1264-1272,
1993[Abstract/Free Full Text].
22.
Murry, CE,
Jennings RB,
and
Reimer KA.
Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.
Circulation
74:
1124-1136,
1986[Abstract/Free Full Text].
23.
Nony, PA,
Scallet AC,
Rountree RL,
Ye X,
and
Binienda Z.
Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning."
Metab Brain Dis
14:
83-94,
1999[ISI][Medline].
24.
Ockaili, R,
Emani VR,
Okubo S,
Brown M,
Krottapalli K,
and
Kukreja RC.
Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide.
Am J Physiol Heart Circ Physiol
277:
H2425-H2434,
1999[Abstract/Free Full Text].
25.
Riepe, MW,
Esclaire F,
Kasischke K,
Schreiber S,
Nakase H,
Kempski O,
Ludolph AC,
Dirnagl U,
and
Hugon J.
Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning." J
Cereb Blood Flow Metab
17:
257-264,
1997[ISI][Medline].
26.
Riepe, MW,
and
Ludolph AC.
Chemical preconditioning: a cytoprotective strategy.
Mol Cell Biochem
174:
249-254,
1997[ISI][Medline].
27.
Riepe, MW,
Niemi WN,
Megow D,
Ludolph AC,
and
Carpenter DO.
Mitochondrial oxidation in rat hippocampus can be preconditioned by selective chemical inhibition of succinate dehydrogenase.
Exp Neurol
138:
15-21,
1996[ISI][Medline].
28.
Schultz, JE,
Hsu AK,
and
Gross GJ.
Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors.
Circulation
97:
1282-1289,
1997[Abstract/Free Full Text].
29.
Schultz, JEJ,
Qian YZ,
Gross GJ,
and
Kukreja RC.
Specific ATP-sensitive potassium channel antagonist 5-hydroxydecanoate blocks ischemic preconditioning in the rat heart.
J Mol Cell Cardiol
29:
1055-1060,
1997[ISI][Medline].
30.
Sugino, T,
Nozaki H,
and
Hashimoto H.
Activation of mitogen-activated protein kinases in gerbil hippocampus with ischemic tolerance induced by 3-nitropropionic acid.
Neurosci Lett
278:
101-104,
2000[ISI][Medline].
31.
Sugino, T,
Nozaki Y,
Takagi Y,
and
Hashimoto N.
3-Nitropropionic acid induces ischemic tolerance in gerbil hippocampus in vivo.
Neurosci Lett
259:
9-12,
1999[ISI][Medline].
32.
Tritto, I,
D'Andrea D,
Eramo N,
Scognamiglio A,
De Simone C,
Violante A,
Esposito A,
Chiariello M,
and
Ambrosio G.
Oxygen radicals can induce preconditioning in rabbit hearts.
Circ Res
80:
743-748,
1997[Abstract/Free Full Text].
33.
von Arnim, CA,
Timmler M,
Ludolph AC,
and
Riepe MW.
Adenosine receptor up-regulation: initiated upon preconditioning but not upheld.
Neuroreport
11:
1223-1226,
2000[ISI][Medline].
34.
Wang, Y,
Hirai K,
and
Ashraf M.
Activation of mitochondrial ATP-sensitive K(+) channel for cardiac protection against ischemic injury is dependent on protein kinase C activity.
Circ Res
85:
731-741,
1999[Abstract/Free Full Text].
35.
Wiegand, F,
Liao W,
Busch C,
Castell S,
Knapp F,
Lindauer U,
Megow D,
Meisel A,
Redetzky A,
Ruscher K,
Trendelenburg G,
Victorov I,
Riepe M,
Diener HC,
and
Dirnagl U.
Respiratory chain inhibition induces tolerance to focal cerebral ischemia.
J Cereb Blood Flow Metab
19:
1229-1237,
1999[ISI][Medline].
36.
Xi, L,
Jarrett NC,
Hess ML,
and
Kukreja RC.
Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knockout mice.
Circulation
99:
2157-2163,
1999[Abstract/Free Full Text].
37.
Xi, L,
Salloum F,
Tekin D,
Jarrett NC,
and
Kukreja RC.
Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice.
Am J Physiol Heart Circ Physiol
277:
H2418-H2424,
1999[Abstract/Free Full Text].
38.
Yao, Z,
Auchampach JA,
Pieper GM,
and
Gross GJ.
Cardioprotective effects of monophosphoryl lipid A, a novel endotoxin analog, in the dog.
Cardiovasc Res
27:
832-838,
1993[Abstract/Free Full Text].
39.
Yoshida, KI,
Maaieh MM,
Shipley JB,
Doloresco M,
Bernardo NL,
Qian YZ,
Elliott GT,
and
Kukreja RC.
Monophosphoryl lipid A induces pharmacologic `preconditioning' in rabbit hearts without concomitant expression of 70-kDa heat shock protein.
Mol Cell Biochem
159:
73-80,
1996[ISI][Medline].
Am J Physiol Heart Circ Physiol 280(5):H2406-H2411
0363-6135/01 $5.00
Copyright © 2001 the American Physiological Society
TOP
ABSTRACT
INTRODUCTION
