Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways
Xi-Ming Yang, MD, PhD*,
J. Bradley Proctor, BS*,
Lin Cui, MD*,
Thomas Krieg, MD*,
James M. Downey, PhD* and
Michael V. Cohen, MD, FACC*, ,*
* Physiology
Medicine, University of South Alabama, College of Medicine, Mobile, Alabama, USA
Manuscript received March 17, 2004;
revised manuscript received April 28, 2004,
accepted May 12, 2004.
* Reprint requests and correspondence: Dr. Michael V. Cohen, Department of Physiology, MSB 3050, University of South Alabama, College of Medicine, Mobile, Alabama 36688 (Email: mcohen{at}usouthal.edu).
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Abstract
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OBJECTIVES: An in situ model was used to test whether and how multiple occlusions at reperfusion can protect rabbit myocardium.
BACKGROUND: Recently it was demonstrated that postconditioning in dogs salvaged ischemic myocardium.
METHODS: Control hearts underwent 30-min regional ischemia/3-h reperfusion, whereas in experimental hearts four postconditioning cycles of 30-s occlusion/30-s reperfusion starting 30 s after release of the index coronary occlusion were added in the presence or absence of various cell signaling antagonists.
RESULTS: Postconditioning decreased infarction from 35.4 ± 2.7% of the risk zone in control hearts to 19.8 ± 1.8% (p < 0.05). Six cycles did not result in greater protection. If postconditioning cycles were begun after 10 min of reperfusion, protection was no longer evident. Either the non-selective KATP channel closer glibenclamide or the putatively selective mitochondrial KATP channel antagonist 5-hydroxydecanoate administered 5 min before reperfusion blocked the protection afforded by postconditioning, indicating involvement of the mitochondrial KATP channel. PD98059, a mitogen-activated protein/extracellular-signal regulated kinase (MEK) 1/2 and therefore extracellular-signal regulated kinase (ERK) inhibitor, and N -nitro-L-arginine methyl ester, an antagonist of nitric oxide synthase, infused shortly before reperfusion also aborted the protection afforded by postconditioning. Combined ischemic postconditioning and preconditioning resulted in significantly greater protection than either alone.
CONCLUSIONS: Multiple, short, regional coronary occlusions immediately after prolonged myocardial ischemia are an effective cardioprotective intervention in the rabbit, and the mechanism of protection involves activation of ERK, production of nitric oxide, and opening of mitochondrial KATP channels. These observations suggest that a similar approach could be applied in the cardiac catheterization laboratory to protect reperfused myocardium after primary angioplasty in patients with acute myocardial infarction.
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Abbreviations and Acronyms
| | ERK = extracellular-signal regulated kinase | | 5-HD = 5-hydroxydecanoate | | L-NAME = N-nitro-L-arginine methyl ester | | NO = nitric oxide | | NOS = nitric oxide synthase |
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Ischemic preconditioning is acknowledged to be a robust cardioprotective intervention that salvages ischemic myocardium in experimental animals and probably in humans (1). However, as its name implies, preconditioning must be applied before an ischemic event to be protective, thus limiting its utility. Ischemic preconditioning is not useful for patients presenting to the hospital after onset of their myocardial infarction. Although thrombolysis, emergency angioplasty, or revascularization surgery can effect reperfusion with documented salvage of ischemic myocardium, these procedures are seldom instituted early enough to eliminate infarction. Furthermore, it is thought that reperfusion itself, although required for salvage, actually contributes to the injury (2–6). Therefore, an intervention is needed that can supplement the reperfusion strategy and attenuate reperfusion injury and/or otherwise limit necrosis in the heart.
A pharmacologic approach has met with varying success. The effectiveness of adenosine administered at reperfusion is very controversial (7–10), and we have been unable to document any protection in our rabbit model (11). On the other hand, the adenosine A1/A2A agonist AMP579 when administered at reperfusion has consistently reduced infarction in all animal heart models tested (11–15). A structurally similar A1/A2 adenosine agonist 5'-(N-ethylcarboxamido) adenosine or NECA was equally protective, and the effect was dependent on phosphatidylinositol 3 (PI3)-kinase, extracellular-signal regulated kinase (ERK), and nitric oxide (NO) (16). We recently reported that CGX-1051, a peptide isolated from the venom of the cone snail, could also salvage myocardium when administered shortly before the onset of reperfusion (17). Several other agents appear to be protective when given to isolated heart models. These include bradykinin (18), cardiotrophin-1 (19), insulin (20), and transforming growth factor-beta-1 (21). Protection with these compounds is generally dependent on PI3-kinase and ERK. However, none of these agents has been validated in an in situ model, which would be required before clinical testing could be considered.
Very recently Zhao et al. reported a most improbable observation (22). They noted that several brief coronary occlusions after a 60-min occlusion in dogs significantly reduced infarct size. This postconditioning protocol has clinical appeal. Because urgent angioplasty is rapidly becoming the principal reperfusion treatment for acute myocardial infarction, it would not be implausible to produce several brief coronary occlusions immediately after the occluded artery is opened. Thus we wondered if ischemic postconditioning could be demonstrated in a second animal model, how its protection compared with that of ischemic preconditioning, and if elements of the signaling pathway leading to protection were at all similar to those already documented for pharmacologic agents that protect when infused at reperfusion.
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Methods
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All procedures were approved by the Institutional Animal Care and Use Committee and were in accordance with recommendations published in the Guide for the Care and Use of Laboratory Animals (National Academic Press, Washington, DC, 1996).
New Zealand White rabbits of either gender weighing between 1.5 and 2.6 kg were anesthetized with intravenous sodium pentobarbital (30 mg/kg). Throughout the experiment, additional anesthesia was administered as needed (5 to 15 mg pentobarbital/15 min). A heating pad maintained rectal temperature between 38.5°C and 39.5°C. Animals were intubated through a tracheotomy and ventilated with 95% O2/5% CO2 with the aid of a mechanical ventilator (MD Industries, Mobile, Alabama). Arterial pH and oxygen and carbon dioxide tensions were maintained within the physiologic range (blood gas analyzer ABL 5, Radiometer, Copenhagen, Denmark). Catheters filled with heparinized saline (10 U/ml) were placed into the left carotid artery to monitor arterial blood pressure and to withdraw blood samples and into the right jugular vein to administer drugs. After left thoracotomy, a major branch of the left coronary artery was surrounded with a suture to form a snare. The rabbits were allowed to stabilize for 20 min after surgery before the protocols were begun.
Protocols.
Hearts of 13 experimental groups experienced 30 min of regional ischemia (Fig. 1), whereas hearts of four other groups experienced 45 min of regional ischemia (Fig. 2). In all hearts, reperfusion after the occlusion lasted for 3 h. Control hearts had only this occlusion and reperfusion. For ischemically preconditioned rabbits, 5-min occlusion/10-min reperfusion immediately preceded the long ischemia. In postconditioning rabbits, four or six cycles of 30-s occlusion/30-s reperfusion started 30 s after release of the indicated long ischemia. All drugs, glibenclamide (0.3 mg/kg), 5-hydroxydecanoate (5-HD) (5 mg/kg), PD98059 (0.3 mg/kg), and N-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), were given as intravenous boluses just 5 min before the onset of reperfusion. These doses have previously been used by us (17) and others (23–26) to selectively block the target. In four additional groups, each of these four tool drugs was infused alone just before reperfusion in the absence of any postconditioning stimulus to determine the effect of the drugs themselves. In one last group, four cycles delayed, the postconditioning cycles were delayed for 10 min after the onset of reperfusion.
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Figure 1 Experimental protocols for animal groups exposed to 30-min coronary artery occlusions. Glib = glibenclamide; 5-HD = 5-hydroxydecanoate; L-NAME = N-nitro-L-arginine methyl ester; PC = ischemic preconditioning.
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Figure 2 Experimental protocols for animal groups exposed to 45-min coronary artery occlusions. PC = ischemic preconditioning.
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Risk zone and infarct size.
After completion of studies, all hearts were excised, suspended by the aortic root from a Langendorff apparatus, and perfused with 0.9% saline. The coronary snare was retightened, and 2- to 9-µm fluorescent microspheres (Duke Scientific, Palo Alto, California) were infused to delineate the area at risk as the nonfluorescent region. Hearts were frozen, cut into 2-mm transverse slices, incubated for 20 min in 1% triphenyltetrazolium chloride (pH 7.4, 37°C), and then immersed in 10% formalin. The borders between fluorescent and nonfluorescent regions were marked under ultraviolet light to identify the risk zone. Infarct and risk zone areas were planimetered, and volumes calculated. Infarct size is presented as a percent of risk zone.
Materials.
All drugs were obtained from Sigma Chemical Co. (St. Louis, Missouri). Glibenclamide and PD98059 were dissolved in dimethyl sulfoxide. The 5-HD and L-NAME were dissolved in 0.9% saline.
Statistics.
Data are expressed as mean ± SEM. One-way analysis of variance combined with Tukey's post hoc test was used to test for differences in infarct size and baseline hemodynamics between groups. Temporal differences in hemodynamic variables in any given group were analyzed with one-way repeated measures analysis of variance, and Tukey's post hoc test was used to examine differences between measurements at any given time point and baseline observations. Infarct sizes were plotted against risk zone volumes for all groups, and regression lines for groups with interventions were compared with the regression line for the control group by analysis of covariance with Bonferroni's correction for multiple comparisons. For all tests, p < 0.05 was considered significant.
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Results
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Hemodynamics.
No differences in basal heart rate or systolic or diastolic pressure were noted among the experimental groups (Table 1). No substantial changes in heart rate and blood pressure were observed after administration of drugs except for an unexpected increase in blood pressure after L-NAME administration in hearts destined to be postconditioned. Blood pressure declined modestly during the coronary occlusion in virtually all groups, with little recovery during reperfusion.
Infarct size.
There was no significant difference in body weight, heart weight, or risk zone volume between the groups (Table 2). In control hearts (30-min occlusion), infarct size was 35.4 ± 2.7% of the risk zone (Fig. 3). Four postconditioning cycles starting 30 s after release of the 30-min coronary occlusion significantly decreased infarction (19.8 ± 1.8%, p < 0.05 vs. control). Six cycles did not result in greater protection (19.8 ± 1.6% infarction). However, if four postconditioning cycles were started 10 min after release of the 30-min occlusion, there was no longer any protection (34.5 ± 1.7% infarction). Either glibenclamide, a non-selective adenosine triphosphate-sensitive potassium (KATP) channel closer, or 5-HD, a selective mitochondrial KATP channel antagonist, blocked the protection of four cycles (32.8 ± 2.3% and 35.8 ± 4.8% infarction, respectively), indicating that the opening of mitochondrial KATP channels was involved in the protective mechanism (Fig. 4). PD98059, a mitogen-activated protein/extracellular-signal regulated kinase (MEK) 1/2 and therefore ERK inhibitor, and L-NAME, an antagonist of NO synthase (NOS), also aborted protection (44.8 ± 3.1% and 45.1 ± 2.3% infarction, respectively). For comparison, hearts preconditioned with ischemia were also treated with the same dose of PD98059 just before reperfusion. As seen in Figure 3, the expected protective effect of preconditioning was not affected (13.4 ± 3.9% infarction of the risk zone). None of the four tool drugs administered at reperfusion had any independent effect on infarct size (glibenclamide 42.2 ± 6.2%, 5-HD 33.6 ± 6.0%, PD98059 34.1 ± 3.7%, and L-NAME 37.0 ± 3.6%) (Fig. 4). Infarct sizes were plotted against risk zone volumes for all groups. The regression lines for postconditioned hearts were different from the regression line for control hearts (p < 0.001), whereas there was no difference between control hearts and those postconditioned hearts also treated with either PD98059, L-NAME, glibenclamide, or 5-HD (Fig. 5).
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Figure 3 Infarct size in in situ rabbit hearts. All animals had a 30-min coronary occlusion and 3-h reperfusion. Open circles represent individual experiments, closed circles depict group means with SEM. Both four and six immediate postconditioning cycles protected ischemic hearts, whereas delayed postconditioning elicited no protection. PD98059 did not block the protective effect of ischemic preconditioning. *p < 0.05 versus control.
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Figure 4 Infarct size in in situ rabbit hearts. All animals had a 30-min coronary occlusion and 3-h reperfusion. Open circles represent individual experiments, closed circles depict group means with SEM. Multiple cycles of immediate postconditioning limited infarct size, whereas glibenclamide (Glib), 5-hydroxydecanoate (5-HD), PD98059, and N-nitro-L-arginine methyl ester (L-NAME) blocked their protection. The tool drugs alone had no effect. *p < 0.05 versus other groups.
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Figure 5 Infarct size plotted against risk zone volume for control hearts and hearts with four cycles of postconditioning alone or after treatment with either PD98059, glibenclamide (Glib), N-nitro-L-arginine methyl ester (L-NAME), or 5-hydroxydecanoate (5-HD). Regression lines for the control group and postconditioned hearts treated with PD98059, Glib, L-NAME, or 5-HD were significantly different from that for hearts subjected only to postconditioning (p < 0.001).
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When regional ischemia was extended to 45 min in control hearts, infarction increased to 61.7 ± 2.2% of the risk zone (Fig. 6), and four postconditioning cycles resulted in significant salvage (39.6 ± 4.2% infarction, p < 0.05). A single preconditioning cycle of 5-min occlusion/10-min reperfusion before the 45-min ischemia also was protective (35.1 ± 4.0% infarction, p < 0.05). The combination of postconditioning and preconditioning resulted in even greater protection than either alone (22.5 ± 3.1% infarction, p < 0.05 vs. either ischemic preconditioning or four cycles).
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Figure 6 Infarct size in in situ rabbit hearts. All animals had a 45-min coronary occlusion and 3-h reperfusion. Open circles represent individual experiments, closed circles depict group means with SEM. Four postconditioning cycles resulted in significant salvage. A single preconditioning (PC) cycle of 5-min occlusion/10-min reperfusion before the 45-min ischemia also was protective. The combination of ischemic postconditioning and preconditioning resulted in even greater protection than either alone. *p < 0.05 versus control; **p < 0.05 versus PC and four cycles.
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Discussion
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A major goal of cardiovascular research is currently the identification of a reliable cardioprotection intervention that can salvage ischemic myocardium. Preconditioning was introduced in 1986 (27), and we know a lot about the signaling pathways leading to the protection afforded by preconditioning (1,28,29), although the identity of its end-effector has been quite elusive. Unfortunately, the clinical value of preconditioning itself is limited. On the other hand, an intervention that could be applied just before or at reperfusion would have great clinical appeal. Although several pharmacologic agents that appear to limit reperfusion injury have been identified (11,12,16,19–21), none of these is available for clinical use. The recent report about repetitive, brief postconditioning ischemia (22), which could easily be produced in patients undergoing angioplasty to open infarct arteries, again raises hope that a simple cardioprotective intervention could produce salutary clinical effects.
The initial investigation by Zhao et al. (22) demonstrated that three cycles of 30-s occlusion/30-s reperfusion starting 30 s after release of a 60-min coronary occlusion in open-chest dogs decreased infarction by 40%, equivalent to the effect of preconditioning. In our rabbit model, four cycles decreased infarction by 43%, whereas increasing the number of cycles did not increase the amount of salvaged tissue. We did not determine the minimum number of cycles required to reduce infarction. However, we did note that the timing of this postconditioning ischemia was critical. If the intervention were delayed for only 10 min, protection was lost. Hence, in the rabbit, postconditioning must occur within the first 10 min of reperfusion to be protective. A similar observation was made for AMP579 (30) and CGX-1051 (17) when administered after reperfusion.
Because ischemic postconditioning was protective, we wondered if this protection could be added to that expected after ischemic preconditioning. To test for such an additive effect, the index ischemia was prolonged to 45 min to increase infarct size in control hearts. Under these conditions, both ischemic preconditioning and postconditioning decreased infarction from 62% to comparable levels of 35% to 40% of the risk zone. When the same heart was subjected to both forms of cardioprotection, infarct size declined further to 22%, significantly less than either preconditioning or postconditioning alone. Because each form of cardioprotection has a maximal infarct-sparing effect when applied singly in this protocol, their additive effect when combined implies that their mechanisms of action must differ. This is further supported by the different effects of PD98059 on the protection afforded by ischemic preconditioning and postconditioning.
This study has not uncovered the actual mechanism of postconditioning, However, we have identified several elements of its signal transduction pathway. Both ERK and NO are probably involved. Perhaps not surprisingly, these elements are also thought to be involved in the signaling of several pharmacologic agents that appear to be protective when administered at reperfusion (16,18,19,21). Interestingly Komalavilas et al. (31) noted that in vascular smooth muscle cells protein kinase G activation stimulated phosphorylation of ERK 1/2, and, of course, production of NO by NOS leads to protein kinase G activation. Therefore, NO and ERK may be signaling elements in a common pathway. Additionally both glibenclamide and 5-HD blocked the protection of postconditioning, implying a role for mitochondrial KATP channels. The protection of CGX-1051 that was found to limit infarction in the in situ rabbit heart when given at reperfusion was also dependent on mitochondrial KATP channels (17). Possible involvement of these channels in the protection of other reperfusion agents has not been investigated. Triggering of preconditioning depends on the production of reactive oxygen species by mitochondria after generation of NO and the opening of mitochondrial KATP channels (29). Thus there are some parallels between preconditioning and postconditioning. However, ERK is not part of preconditioning's signaling (32), as again shown in this study.
Thus, the protection afforded by postconditioning has now been observed in two animal models—dog and rabbit. The timing of the intervention is critical, and its protection can be added to that of preconditioning. The mechanism of the protection is uncertain. It is not yet known if ion fluxes or mitochondrial or cell swelling is affected. An initial report suggests that postconditioning reduces superoxide production by reperfused myocardium (22), but we do not know if that is the cause or the result of the protection. This report not only has confirmed the efficacy of postconditioning but also has revealed that its protection is dependent on cellular signal transduction pathways. In fact, most of these critical signaling entities are also involved in preconditioning. Perhaps more notable, other pharmacologic agents successful at protecting ischemic myocardium when administered at reperfusion use these same pathways leading to activation of the final effector.
This procedure of postconditioning could be safely and readily adapted for clinical use. After initial reperfusion of the infarct artery during primary angioplasty in a patient with an acute myocardial infarction, several brief, low-pressure balloon occlusions of the vessel could be performed before the procedure is completed with subsequent additional dilations to obtain grade 3 Thrombolysis In Myocardial Infarction (TIMI) flow and stenting if required. Current catheterization laboratory protocols would not be expected to routinely postcondition the heart, because of the critical requirement for multiple, brief occlusions in the first seconds of reperfusion. This approach has important clinical potential and should be further explored.
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Footnotes
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This study was supported in part by grants HL-20648 and HL-50688 from the Heart, Lung, and Blood Institute of the National Institutes of Health.
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L. Argaud, O. Gateau-Roesch, L. Augeul, E. Couture-Lepetit, J. Loufouat, L. Gomez, D. Robert, and M. Ovize
Increased mitochondrial calcium coexists with decreased reperfusion injury in postconditioned (but not preconditioned) hearts
Am J Physiol Heart Circ Physiol,
January 1, 2008;
294(1):
H386 - H391.
[Abstract]
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S. L. Hale, A. Mehra, J. Leeka, and R. A. Kloner
Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion
Am J Physiol Heart Circ Physiol,
January 1, 2008;
294(1):
H421 - H425.
[Abstract]
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P. Ferdinandy, R. Schulz, and G. F. Baxter
Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning
Pharmacol. Rev.,
December 1, 2007;
59(4):
418 - 458.
[Abstract]
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R. Jiang, A. Zatta, H. Kin, N. Wang, J. G. Reeves, J. Mykytenko, J. Deneve, Z.-Q. Zhao, R. A. Guyton, and J. Vinten-Johansen
PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts
Am J Physiol Heart Circ Physiol,
November 1, 2007;
293(5):
H2845 - H2852.
[Abstract]
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G.-X. Zhang, X.-M. Lu, S. Kimura, and A. Nishiyama
Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation
Cardiovasc Res,
November 1, 2007;
76(2):
204 - 212.
[Abstract]
[Full Text]
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J. Vinten-Johansen, Z.-Q. Zhao, R. Jiang, A. J. Zatta, and G. P. Dobson
Preconditioning and postconditioning: innate cardioprotection from ischemia-reperfusion injury
J Appl Physiol,
October 1, 2007;
103(4):
1441 - 1448.
[Abstract]
[Full Text]
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R. R. Morrison, X. L. Tan, C. Ledent, S. J. Mustafa, and P. A. Hofmann
Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning
Am J Physiol Heart Circ Physiol,
October 1, 2007;
293(4):
H2523 - H2529.
[Abstract]
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H. Sato, R. Bolli, G. D. Rokosh, Q. Bi, S. Dai, G. Shirk, and X.-L. Tang
The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats
Am J Physiol Heart Circ Physiol,
October 1, 2007;
293(4):
H2557 - H2564.
[Abstract]
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S. P. Loukogeorgakis, R. Williams, A. T. Panagiotidou, S. K. Kolvekar, A. Donald, T. J. Cole, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister
Transient Limb Ischemia Induces Remote Preconditioning and Remote Postconditioning in Humans by a KATP Channel Dependent Mechanism
Circulation,
September 18, 2007;
116(12):
1386 - 1395.
[Abstract]
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Hardev Ramandeep Singh Girn, S. Ahilathirunayagam, A. I. D. Mavor, and S. Homer-Vanniasinkam
Reperfusion Syndrome: Cellular Mechanisms of Microvascular Dysfunction and Potential Therapeutic Strategies
Vascular and Endovascular Surgery,
September 1, 2007;
41(4):
277 - 293.
[Abstract]
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L. Gomez, H. Thibault, A. Gharib, J.-M. Dumont, G. Vuagniaux, P. Scalfaro, G. Derumeaux, and M. Ovize
Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice
Am J Physiol Heart Circ Physiol,
September 1, 2007;
293(3):
H1654 - H1661.
[Abstract]
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J. Taki, T. Higuchi, A. Kawashima, M. Fukuoka, D. Kayano, J. F. Tait, I. Matsunari, K. Nakajima, S. Kinuya, and H. W. Strauss
Effect of Postconditioning on Myocardial 99mTc-Annexin-V Uptake: Comparison with Ischemic Preconditioning and Caspase Inhibitor Treatment
J. Nucl. Med.,
August 1, 2007;
48(8):
1301 - 1307.
[Abstract]
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C. Penna, D. Mancardi, R. Rastaldo, G. Losano, and P. Pagliaro
Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling
Cardiovasc Res,
July 1, 2007;
75(1):
168 - 177.
[Abstract]
[Full Text]
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