| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1The Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, London WC1E 6DB; and 2The Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom
Submitted 16 July 2003 ; accepted in final form 5 April 2004
 |
ABSTRACT |
|---|
 TOP ABSTRACT EXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
ischemia-reperfusion; myocardial preconditioning; oxidative stress
Several studies have shown consequences of IPC and pharmacological preconditioning that could be beneficial for mitochondrial function and cell survival in the setting of ischemia-reperfusion. These consequences include 1) reducing mitochondrial calcium load (19, 32, 43); 2) attenuation of the oxidative stress generated at reperfusion (36, 42); 3) improved mitochondrial respiratory function (14, 24); 4) maintaining the integrity of the mitochondrial intermembrane space, which has important implications for mitochondrial respiratory function (8, 29); and 5) reducing mitochondrial cytochrome c release and apoptosis (1). More recently, it has been suggested that the preconditioning stimulus may act as a "trigger" for other downstream effector mechanisms that initiate myocardial preconditioning, with reactive oxygen species (ROS) acting as the mediator, although the end effector of preconditioning remains elusive (3, 13, 37).
A potential target in this scheme may be the mitochondrial permeability transition (mPT), which represents a fundamental event in the pathway to reperfusion-induced cell death (6). The mPT has been shown to be mediated by the opening of a nonspecific large conductance pore of the inner mitochondrial membrane (20). Inducing the mPT permeates the inner mitochondrial membrane, leading to cell death by apoptosis (due to the release of mitochondrial cytochrome c) and necrosis (due to the collapse of the mitochondrial membrane potential and resultant uncoupling of oxidative phosphorylation, which leads to ATP depletion) (30).
Interestingly, the probability of inducing the mPT is increased by the same factors that prevail in the setting of ischemia-reperfusion injury and include oxidative stress, a high mitochondrial calcium and inorganic phosphate load, and ATP depletion (4). Therefore, conditions for inducing the mPT are present during ischemia-reperfusion, and its role in mediating the cell death associated with ischemia-reperfusion injury has been borne out by the fact that we and others have shown that pharmacologically suppressing the mPT in this setting is cardioprotective (16, 18). Because preconditioning has been shown also to modulate factors associated with inducing of the mPT, one might expect it to influence the probability of inducing the mPT in the setting of ischemia-reperfusion injury. We propose that preconditioning protects the myocardium by suppressing the mPT that occurs on reperfusing ischemic myocardium. In this regard, we have recently demonstrated for the first time the modulation of the mPT in the setting of IPC and pharmacological preconditioning (18). We investigated the effect of preconditioning on the mPT indirectly in the isolated perfused heart, and in isolated mitochondria we examined modulation of the mPT directly in the setting of pharmacological preconditioning (18). The objective of the present study was therefore to investigate more directly, using the intact cell, whether preconditioning protects by suppressing the mPT. Because ROS generated within mitochondria on reperfusing ischemic myocardium have been shown to play a pivotal role in both mediating cell death and inducing the mPT (28, 48), we investigated the effects of hypoxic and pharmacological preconditioning using a model in which oxidative stress generated within mitochondria is used to provoke the mPT followed by rigor contracture.
|
EXPERIMENTAL PROCEDURES |
|---|
|
TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
Materials. Diazoxide (Sigma) and glibenclamide (Sigma) were dissolved in DMSO, giving a final concentration of <0.1% DMSO. Cyclosporin A (CsA; Sigma) and N-methyl-4-valine-CsA (gift from Novartis Pharm; Basel, Switzerland) were dissolved in 50% ethanol, giving a final concentration of 0.05% ethanol. HMR-1098 (gift from Dr. J. Downey) and 5-hydroxydecanoate (5-HD; Sigma) were dissolved in distilled water. Tetramethylrhodamine methyl ester (TMRM; Molecular Probes Europe, Leiden, The Netherlands) was dissolved in DMSO. All other agents were of standard analytical grade and quality.
Preparation of adult rat myocytes. Adult rat myocytes were isolated by collagenase perfusion by use of a previously described method with modifications (45). Briefly, after anesthesia with sodium pentobarbital (55 mg/kg ip) and administration of heparin sodium (300 IU), hearts were rapidly excised, placed in ice-cold buffer, and mounted on a nonrecirculating perfusion apparatus. All solutions used were based on a modified calcium-free Krebs-Ringer-HEPES (KRH) buffer (in mM): 116.0 NaCl, 5.4 KCl, 0.4 MgSO4, 20.0 HEPES, 0.9 Na2HPO4, and 5.6 glucose (pH 7.4). The perfusate was bubbled with 100% O2 and maintained at 37°C. The hearts were first perfused at 14 ml/min with KRH buffer containing 1 mg/ml BSA and 3.3 µM EGTA. After 5 min, the hearts were perfused with KRH buffer containing 0.75 mg/ml collagenase (Worthington type II) and 25 µM calcium for 10–15 min. They were finally perfused with KRH buffer containing 50 µM calcium for 5 min. After perfusion, the hearts were removed from the perfusion apparatus, and the atria were trimmed away. The ventricles were minced and underwent several more digestions with collagenase. The cells were then filtered through a nylon mesh and washed with restoration buffer: KRH buffer plus 10 mg/ml BSA, 0.5 mM Na-pyruvate, 5.0 mM taurine, 2.0 mM carnitine, 1.0 mM creatine, and 75 µM calcium. The calcium concentration was gradually increased to 1.25 mM. After isolation, the cells were seeded onto sterilized laminin-coated 25-mm-diameter round coverslips and incubated overnight at 37°C in an atmosphere of 95% air-5% CO2 in M-199 medium (M7653, Sigma) containing 10% fetal calf serum and 1% penicillin-streptomycin (Sigma). The next day, cells were washed and kept in restoration buffer.
Model for induction and detection of the mPT in intact cells. We monitored induction of the mPT in a cellular model of oxidative stress (25). Isolated adult ventricular myocytes, in restoration buffer, were incubated with the fluorescent dye TMRM (3 µM) for 15 min at 37°C, washed, and visualized using confocal fluorescence microscopy. TMRM, a lipophilic cation, accumulates selectively into mitochondria according to the mitochondrial membrane potential. Laser illumination of the TMRM generates ROS from within the mitochondria that provoke the mPT. In this model, induction of the mPT is seen by collapse of the mitochondrial membrane potential (9, 22). Oxidative stress generated on reperfusing ischemic myocardium also involves the excess production of ROS from within the mitochondria, and this model should therefore simulate the events associated with reperfusion-induced cell injury. This model represents a widely reported and reliable way to reproducibly induce the loss of mitochondrial membrane potential, which has been unequivocally identified as a reflection of the mPT (7, 9, 11, 21, 22, 25, 47). The relatively high concentration of TMRM in the mitochondria causes autoquenching of fluorescence, such that the fluorescence signal becomes a nonlinear function of dye concentration; therefore, in this model, mitochondrial membrane depolarization results in loss of dye into the cytosol where the signal increases (2, 10). Laser-induced oxidative stress was applied until the mPT had been provoked (indicated by collapse of the mitochondrial potential) and continued until rigor contracture had been induced. The time taken to induce the mPT and the additional time required to induce rigor contracture (signaling ATP depletion) were measured.
To confirm the efficacy of the protocol in inducing the mPT, we also examined the effect of laser-induced oxidative stress on the redistribution of the fluorescent dye calcein from the mitochondrial matrix. We used an established method for detecting the induction of the mPT in the intact cell (26, 38) in which adult rat myocytes were incubated with calcein-AM (1.0 µmol/l) and cobalt chloride (CoCl2, 1.0 mmol/l). The cobalt quenches cytosolic calcein so that only the mitochondrial dye is seen. In this model, the mPT is indicated by the redistribution of the calcein signal out of the mitochondrial matrix. This was quantified by measuring the ratio of the standard deviation to the mean of the fluorescence signal. Localization of the signal to mitochondria results in a signal in which pixels over mitochondria are very bright and pixels in the cytosol are very dark (SD is high). Redistribution of dye will lead to a decrease in mean signal as the calcein is quenched but also a loss of significant difference as the distribution of signal becomes increasingly uniform.
Confocal fluorescence imaging and analysis. The coverslip containing the myocytes was placed in a chamber and mounted on the stage of a Zeiss 510 CLSM confocal microscope equipped with x40 oil immersion, quartz objective lens (numerical aperture 1.3). For TMRM fluorescence, the cells were illuminated by use of the 543-nm emission line of a HeNe laser. For all photosensitization experiments, all conditions of the confocal imaging system (laser power; confocal pinhole, set to give an optical slice of 1 µm; pixel dwell time; and detector sensitivity) were identical to ensure comparability between experiments. The fluorescence of TMRM was collected using a 585-nm long-pass filter. Images were analyzed by use of Zeiss software (LSM 2.8). For measurement of calcein fluorescence, cells were illuminated using the 488-nm emission line of an Argon laser, and fluorescence was measured by use of a 505-nm long-pass filter.
Treatment protocols. After being loaded with TMRM, cells were randomly assigned to the following treatment groups.
Treatment group 1 is control (n = 18) or incubation with 0.05% ethanol vehicle (n = 6) or 0.1% DMSO vehicle (n = 6).
Treatment groups 2 and 3 are CsA (0.2 µM, a known inhibitor of the mPT; n = 12) (5) and N-methyl-4-valine-CsA (0.4 µM, a known inhibitor of the mPT that does not inhibit the phosphatase calcineurin; n = 12), respectively (39).
Treatment group 4 is hypoxic preconditioning (HP; n = 12). Cells were incubated for two periods of 10 min at 37°C in anoxic buffer composed of (in mM) 137.0 NaCl, 12.0 KCl, 0.49 MgCl2, 4.0 HEPES, 0.9 CaCl2, 1.0 Na-dithionite, 20.0 2-deoxyglucose, and 20.0 lactate (pH 6.5) with an intervening 30-min reoxygenation in restoration buffer before undergoing the TMRM-induced oxidative stress protocol.
Treatment groups 5 and 6 are HP in the presence of either 5-HD (100 µM, a purported mKATP channel blocker; n = 6) or glibenclamide (10 µM, a nonspecific mKATP channel blocker; n = 6), respectively.
Treatment group 7 is diazoxide (30 µM, a purported mKATP channel opener; n = 6) (15).
Treatment groups 8, 9, and 10 are diazoxide in the presence of either 5-HD (n = 6), glibenclamide (n = 6), or HMR-1098 (10 µM, a specific sarcolemmal KATP channel blocker; n = 6), respectively.
Treatment group 11 is nicorandil (100 µM, another purported mKATP channel opener; n = 12).
Treatment groups 12 and 13 are nicorandil in the presence of either 5-HD (n = 6) or glibenclamide (n = 6), respectively.
Treatment groups 14, 15, and 16 are 5-HD (n = 6), glibenclamide (n = 6), or HMR-1098 alone (n = 6), respectively.
In all groups, the cells were incubated for 20 min with the treatment drug(s) before the TMRM-induced oxidative stress protocol.
Statistical analysis. All values are expressed as means ± SE. Times taken to induce global mitochondrial depolarization and rigor contracture were analyzed by one-way ANOVA and Fisher's protected least significant difference test for multiple comparisons. Differences were considered significant when P < 0.05.
|
RESULTS |
|---|
|
TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
|
|
|
|
|
|
With respect to pharmacological preconditioning, diazoxide in the presence of either glibenclamide or 5-HD also abolished both the delay in the time taken to induce the mPT (528.3 ± 28.5 s with diazoxide vs. 261.7 ± 24.1 s with glibenclamide and 283.3 ± 14.4 s with 5-HD; P < 0.001; Fig. 6) and the delay in the time taken to induce rigor contracture (1,095.6 ± 102.4 s with diazoxide vs. 543.4 ± 47.1 s with glibenclamide and 664.0 ± 48.3 s with 5-HD; P < 0.001; Fig. 7). Furthermore, nicorandil in the presence of either glibenclamide or 5-HD also abolished both the delay in the time taken to induce the mPT (386.1 ± 33.4 s with nicorandil vs. 256.1 ± 25.6 s with glibenclamide and 249.1 ± 36.1 s with 5-HD; P < 0.001; Fig. 6) and the delay in the time taken to induce rigor contracture (967.6 ± 61.8 s with nicorandil vs. 482.3 ± 48.1 s with glibenclamide and 661.0 ± 77.4 s with 5-HD; P < 0.001; Fig. 7).
However, the specific sarcolemmal KATP channel blocker HMR-1098 did not abolish the effects of diazoxide on either the time taken to induce the mPT [528.5 ± 28.5 s with diazoxide vs. 485.9 ± 11.5 s with HMR-1098; P = not significant (NS); Fig. 6] or the time taken to induce rigor contracture (1,095.6 ± 102.4 s with diazoxide vs. 1,076.8 ± 30.3 s with HMR-1098; P = NS; Fig. 7). Given alone, the KATP channel blockers did not influence either the time required to induce the mPT (216.3 ± 13.5 s in control vs. 239.4 ± 22.3 s with glibenclamide, 197.3 ± 11.2 s with 5-HD, and 216.3 ± 13.5 s with HMR-1098; P = NS; Figs. 3 and 6) or the time taken to induce rigor contracture (636.1 ± 26.4 s in control vs. 732.6 ± 77.3 s with glibenclamide, 496.4 ± 28.2 s with 5-HD, and 729.4 ± 18.8 s with HMR-1098; P = NS; Figs. 4 and 7).
|
DISCUSSION |
|---|
|
TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
The present study extends previous work we have undertaken (18) in which we showed for the first time that cardioprotection arising from either ischemic or pharmacological preconditioning may be due to suppression of the mPT that normally occurs on reperfusing ischemic myocardium. In that study, we demonstrated in the isolated perfused rat heart that pharmacologically inducing the mPT at reperfusion reversed the protection induced by both ischemic and pharmacological preconditioning, using infarct size as the measured end point of cell death. This finding suggested to us that preconditioning may manifest its protection by suppressing the mPT but did not directly prove it. To prove suppression of the mPT as the mechanism responsible for preconditioning-induced protection, it was imperative to assess the consequences of preconditioning on the mPT directly. In this regard, we and others (18, 27) have shown that diazoxide, an agent used to pharmacologically precondition the myocardium, was able to inhibit the mPT associated with mitochondrial calcium loading, a major contributor to reperfusion-induced cell death. An interesting study by Xu et al. (46) in myocytes had previously shown that pharmacologically inducing the mPT abrogated the protection associated with calcium-induced preconditioning. However, the authors failed to examine the consequence of calcium-induced preconditioning on the mPT directly. In the present study, we examined directly the effect of hypoxic and pharmacological preconditioning on the mPT in the intact cell.
The effects of hypoxic and pharmacological preconditioning (using diazoxide or nicorandil, purported openers of the mKATP channel) on suppressing the mPT and protecting against rigor contracture in the face of oxidative stress were abrogated in the presence of 5-HD and glibenclamide, agents that have been shown to antagonize the putative mKATP channel. Controversy surrounds the nature of protection associated with agents such as diazoxide and pinacidil that are reported to act via the putative mKATP channel (17, 35). Methods employed in investigating the role of the mKATP channel have relied heavily on using pharmacological agents to manipulate the mKATP channel (15, 31). It is clear that agents such as diazoxide or pinacidil do protect the myocardium from ischemia-reperfusion injury, but because they also have nonspecific effects on mitochondrial function, the mechanism through which they cardioprotect may be independent of mKATP channel activation. For example, as far back as 1969, it was noted that diazoxide can inhibit the electron transport carrier II, succinate dehydrogenase (SDH) (41). Several studies have confirmed this effect of diazoxide on SDH and have shown that this effect is not restricted to diazoxide and may also apply to pinacidil (17, 35). Even abrogation by 5-HD of the cardioprotective effect induced by diazoxide or pinacidil may be explained by a nonspecific effect of 5-HD on mitochondrial function (17). Recently, it has been shown that 5-HD can be metabolized to a fatty acid that acts as a substrate for SDH, thereby antagonizing the inhibitory effects of diazoxide or pinacidil on SDH rather than antagonizing at the mKATP channel (17). Furthermore, it has been demonstrated that inhibition of SDH, using a low dose of 3-nitropropionic acid (3-NPA), protected rabbit hearts from infarction, an effect abolished by 5-HD (34).
By inhibiting electron flow through the electron transport chain, agents such as diazoxide or pinacidil may be expected to generate ROS from complexes I or III (12). It is exciting to consider that this may be the source for the ROS that have been recently implicated as mediating preconditioning-induced protection through their activation of prosurvival kinases. (3, 13, 37). In this regard, it has been shown that in cerebral tissue, 3-NPA, through its inhibition of SDH, caused a burst of ROS, which were then shown to mediate preconditioning-type protection (44).
It may transpire therefore that ischemic and pharmacological preconditionings (using agents such as diazoxide and nicorandil) induce cardioprotection through their nonspecific effects on mitochondrial function, including respiratory chain inhibition, and ROS release from the mitochondria. We propose that preconditioning confers beneficial effects on mitochondrial function and calcium handling that result in mitochondria that are better equipped or "preconditioned" to withstand the crucial phase of reperfusion, which is associated with an influx of calcium into the mitochondria and oxidant stress (see Fig. 8). Although these events would normally precipitate the mPT and cell death, the events of preconditioning reduce the probability of inducing the mPT at reperfusion and so protect the heart from cell death.
|
|
GRANTS |
|---|
|
TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
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.
|
REFERENCES |
|---|
|
TOPABSTRACTEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  C. L. Quinlan, A. D. T. Costa, C. L. Costa, S. V. Pierre, P. Dos Santos, and K. D. Garlid Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H953 - H961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nishino, I. G. Webb, S. M. Davidson, A. I. Ahmed, J. E. Clark, S. Jacquet, A. M. Shah, T. Miura, D. M. Yellon, M. Avkiran, et al. Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse Circ. Res., August 1, 2008; 103(3): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Rodrigo and N. J. Samani Ischemic preconditioning of the whole heart confers protection on subsequently isolated ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H524 - H531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Toda, T. Kadono, M. Hoshiai, Y. Eguchi, S. Nakazawa, H. Nakazawa, N. Higashijima, and H. Ishida Na+/H+ exchanger inhibitor cariporide attenuates the mitochondrial Ca2+ overload and PTP opening Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3517 - H3523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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] [PDF]
|
|
|
|
|
|
P. A. Townsend, S. M. Davidson, S. J. Clarke, I. Khaliulin, C. J. Carroll, T. M. Scarabelli, R. A. Knight, A. Stephanou, D. S. Latchman, and A. P. Halestrap Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H928 - H938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Lim, S. M. Davidson, D. J. Hausenloy, and D. M. Yellon Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore Cardiovasc Res, August 1, 2007; 75(3): 530 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Khaliulin, S. J. Clarke, H. Lin, J. Parker, M.-S. Suleiman, and A. P. Halestrap Temperature preconditioning of isolated rat hearts - a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore J. Physiol., June 15, 2007; 581(3): 1147 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Hamid, H. S. Bower, and G. F. Baxter Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2598 - H2606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Brennan, R. G. Berry, M. Baghai, M. R. Duchen, and M. J. Shattock FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation Cardiovasc Res, November 1, 2006; 72(2): 322 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ruiz-Meana, D. Garcia-Dorado, E. Miro-Casas, A. Abellan, and J. Soler-Soler Mitochondrial Ca2+ uptake during simulated ischemia does not affect permeability transition pore opening upon simulated reperfusion Cardiovasc Res, September 1, 2006; 71(4): 715 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Davidson and M. R. Duchen Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance Cardiovasc Res, July 1, 2006; 71(1): 10 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole Cardiovasc Res, May 1, 2006; 70(2): 191 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Garcia-Dorado, A. Rodriguez-Sinovas, M. Ruiz-Meana, J. Inserte, L. Agullo, and A. Cabestrero The end-effectors of preconditioning protection against myocardial cell death secondary to ischemia-reperfusion Cardiovasc Res, May 1, 2006; 70(2): 274 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Diaz and G. J. Wilson Studying ischemic preconditioning in isolated cardiomyocyte models Cardiovasc Res, May 1, 2006; 70(2): 286 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Marcil, K. Bourduas, A. Ascah, and Y. Burelle Exercise training induces respiratory substrate-specific decrease in Ca2+-induced permeability transition pore opening in heart mitochondria Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1549 - H1557. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Bovill Intravenous Anesthesia for the Patient with Left Ventricular Dysfunction Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2006; 10(1): 43 - 48. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 B. O'Rourke, S. Cortassa, and M. A. Aon Mitochondrial Ion Channels: Gatekeepers of Life and Death Physiology, October 1, 2005; 20(5): 303 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Madesh, B. J. Hawkins, T. Milovanova, C. D. Bhanumathy, S. K. Joseph, S. P. RamachandraRao, K. Sharma, T. Kurosaki, and A. B. Fisher Selective role for superoxide in InsP3 receptor-mediated mitochondrial dysfunction and endothelial apoptosis J. Cell Biol., September 26, 2005; 170(7): 1079 - 1090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shanmuganathan, D. J. Hausenloy, M. R. Duchen, and D. M. Yellon Mitochondrial permeability transition pore as a target for cardioprotection in the human heart Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H237 - H242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition Cardiovasc Res, May 1, 2005; 66(2): 222 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res, May 1, 2005; 66(2): 233 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wang, D. A. Liem, T. M. Vondriska, H. M. Honda, P. Korge, D. M. Pantaleon, X. Qiao, Y. Wang, J. N. Weiss, and P. Ping Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1290 - H1295. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
6/group. mPTP, mPT pore. *P < 0.001 and #P < 0.005.
