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Division of Cardiology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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.
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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.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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.
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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.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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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.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-51045 and HL-59469 (to R. C. Kukreja).
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FOOTNOTES |
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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.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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R. Natarajan, F. N. Salloum, B. J. Fisher, E. D. Ownby, R. C. Kukreja, and A. A. Fowler 3rd Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1571 - H1580. [Abstract] [Full Text] [PDF]
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 N. Turan, C. Csonka, T. Csont, Z. Giricz, G. Fodor, P. Bencsik, M. Gyongyosi, I. Cakici, and P. Ferdinandy The role of peroxynitrite in chemical preconditioning with 3-nitropropionic acid in rat hearts Cardiovasc Res, May 1, 2006; 70(2): 384 - 390. [Abstract] [Full Text] [PDF]
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L. Mabanta, P. Valane, J. Borne, and M. D. Frame Initiation of remote microvascular preconditioning requires KATP channel activity Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H264 - H271. [Abstract] [Full Text] [PDF]
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 D. A. Brown, A. J. Chicco, K. N. Jew, M. S. Johnson, J. M. Lynch, P. A. Watson, and R. L. Moore Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat J. Physiol., December 15, 2005; 569(3): 913 - 924. [Abstract] [Full Text] [PDF]
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R. Ockaili, R. Natarajan, F. Salloum, B. J. Fisher, D. Jones, A. A. Fowler III, and R. C. Kukreja HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H542 - H548. [Abstract] [Full Text] [PDF]
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D. J. Hausenloy, D. M. Yellon, S. Mani-Babu, and M. R. Duchen Preconditioning protects by inhibiting the mitochondrial permeability transition Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H841 - H849. [Abstract] [Full Text] [PDF]
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 B. O'Rourke Evidence for Mitochondrial K+ Channels and Their Role in Cardioprotection Circ. Res., March 5, 2004; 94(4): 420 - 432. [Abstract] [Full Text] [PDF]
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J. Minners, C. J. McLeod, and M. N. Sack Mitochondrial plasticity in classical ischemic preconditioning--moving beyond the mitochondrial KATP channel Cardiovasc Res, July 1, 2003; 59(1): 1 - 6. [Abstract] [Full Text] [PDF]
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P. P. Dzeja, P. Bast, C. Ozcan, A. Valverde, E. L. Holmuhamedov, D. G. L. Van Wylen, and A. Terzic Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1048 - H1056. [Abstract] [Full Text] [PDF]
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K. H H Lim, S. A Javadov, M. Das, S. J Clarke, M-S. Suleiman, and A. P Halestrap The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration J. Physiol., December 15, 2002; 545(3): 961 - 974. [Abstract] [Full Text] [PDF]
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J. Han, N. Kim, H. Joo, and E. Kim Ketamine abolishes ischemic preconditioning through inhibition of KATP channels in rabbit hearts Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H13 - H21. [Abstract] [Full Text] [PDF]
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C. Ozcan, M. Bienengraeber, P. P. Dzeja, and A. Terzic Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H531 - H539. [Abstract] [Full Text] [PDF]
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