Published online before print July 19, 2001, doi: 10.1161/hh1501.094266
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© 2001 American Heart Association, Inc.
Integrative Physiology |
Acetylcholine, Bradykinin, Opioids, and Phenylephrine, but not Adenosine, Trigger Preconditioning by Generating Free Radicals and Opening Mitochondrial KATP Channels
From the Departments of Physiology (M.V.C., X.-M.Y., G.S.L., G.H., J.M.D.) and Medicine (M.V.C.), College of Medicine, University of South Alabama, Mobile, Alabama, and Department of Pathophysiology (G.H.), University of Essen Medical School, Essen, Germany.
Correspondence to Michael V. Cohen, MD, Department of Physiology, MSB 3050, College of Medicine, University of South Alabama, Mobile, AL 36688-0002. E-mail mcohen{at}usamail.usouthal.edu
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Abstract |
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Abstract— It has been assumed that all Gi-coupled receptors trigger the protective action of preconditioning by means of an identical intracellular signaling pathway. To test this assumption, rabbit hearts were isolated and perfused with Krebs buffer. All hearts were subjected to a 30-minute coronary artery occlusion followed by 120 minutes of reperfusion. Risk area was measured with fluorescent particles and infarct size with triphenyltetrazolium chloride staining. Control hearts showed 29.1±2.8% infarction of the risk zone. A 5-minute infusion of acetylcholine (0.55 mmol/L) beginning 15 minutes before the 30-minute occlusion resulted in significant protection (9.2±2.7% infarction). This protection could be blocked by administration of 300 µmol/L N-2-mercaptopropionyl glycine (MPG), a free radical scavenger, or by 200 µmol/L 5-hydroxydecanoate (5-HD), a mitochondrial KATP antagonist, for 15 minutes beginning 5 minutes before the acetylcholine infusion (35.2±3.9% and 27.8±2.4% infarction, respectively). Similar protection was observed with other known triggers, ie, bradykinin (0.4 µmol/L), morphine (0.3 µmol/L), and phenylephrine (0.1 µmol/L), and in each case protection was completely abrogated by either MPG or 5-HD. In contrast, protection by adenosine or its analog N6-(2-phenylisopropyl) adenosine could not be blocked by either MPG or 5-HD. Therefore, whereas most of the tested agonists trigger protection by a pathway that requires opening of mitochondrial KATP channels and production of free radicals, the protective action of adenosine is not dependent on either of these steps. Hence, it cannot be assumed that all Gi-coupled receptors use the same signal transduction pathways to trigger preconditioning.
Key Words: acetylcholine • adenosine • free radicals • KATP channels • preconditioning
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Introduction |
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Ischemic preconditioning has great clinical potential. This potent cardioprotective intervention renders the ischemic heart very resistant to infarction.1 An understanding of the mechanism of this phenomenon would facilitate its translation from the experimental laboratory to the patient care arena. Various agonists such as adenosine, bradykinin, and opioids released by ischemic myocardial cells bind to receptors on the cell surface, resulting in G protein activation and stimulation of phospholipases C and D.2 In turn, protein kinase C (PKC) and perhaps a kinase cascade involving p38 mitogen-activated protein kinase (MAPK) is activated.2 However, there is much we do not know. Probably most obvious is our inability to identify an end effector that would ultimately be responsible for the protection.
At one point, the mitochondrial ATP-sensitive K+ channel was considered to be a likely candidate for this end effector. However, a recent report from our laboratory suggested that the mitochondrial KATP channel primarily acts as a trigger rather than an end effector, although an additional role as an end effector could not be completely excluded.3 Yao et al4 studied the effect of acetylcholine (ACh), an agonist known to be a preconditioning mimetic,5,6 on free radical production by chick cardiomyocytes. When ACh was added to the cultured myocytes, there was a significant burst in free radical production. This burst was predictably blocked by N-2-mercaptopropionyl glycine (MPG), a free radical scavenger, and interestingly by myxothiazol, an inhibitor of mitochondrial electron transport, indicating that mitochondria were the source of these radicals. Most striking, however, was the observation that the burst of free radicals after exposure of the chick cardiomyocytes to ACh was completely abrogated by 5-hydroxydecanoate (5-HD), a specific antagonist of mitochondrial KATP channels.7 The salutary effect of ACh on cell survival was also reversed by MPG and 5-HD. The authors suggested that ACh was opening mitochondrial KATP channels, which in turn caused the increased production of free radicals. Because the latter had already been shown to precondition the heart and reduce infarct size after coronary occlusion,8,9 presumably by directly activating phospholipases and PKC, it was felt that this could be a mechanism by which agonists might trigger protection. Furthermore, these observations strengthened the proposed role of the KATP channel as a trigger. This close interaction between the KATP channel and free radicals was confirmed when it was noted that free radical scavengers blocked the protection from diazoxide,3 a putative opener of mitochondrial KATP channels.7,10
Because of this unprecedented interaction between receptors, KATP channels, and free radicals, it was considered important to determine whether this association was unique to ACh. Thus, we examined the dependency of ACh protection on free radicals and KATP channels in a clinically relevant rabbit model of myocardial infarction. We studied the effects of other agonists such as adenosine, N6-(2-phenylisopropyl) adenosine (PIA), bradykinin, morphine, and phenylephrine as well.
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Materials and Methods |
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This study was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Academic Press, Washington DC, 1996), and all procedures were approved by the Institutional Animal Care and Use Committee.
Surgical Preparation
New Zealand White rabbits were anesthetized with intravenous sodium pentobarbital (30 mg/kg) and ventilated through a tracheotomy. After a left thoracotomy, a major branch of the left coronary artery was surrounded by a suture, and the two ends were passed through a small vinyl tube to form a snare. Hearts were rapidly excised and perfused in the Langendorff mode with Krebs-Henseleit buffer (in mmol/L, NaCl 118.5, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 24.8, and glucose 10) gassed with 95% O2/5% CO2 and maintained at a pH of 7.35 to 7.45 and a temperature of 37°C. Perfusion pressure was set to 75 mm Hg by adjusting the height of the reservoir. A saline-filled latex balloon connected to a pressure transducer was inserted through the mitral valve into the left ventricle and inflated to set an end-diastolic pressure of 5 mm Hg at baseline. Timed collection of effluent dripping from the heart was used to measure coronary flow.
Protocol
Control hearts were subjected to 30 minutes of coronary artery occlusion and 120 minutes of reperfusion. In hearts treated with agonists, a 5-minute infusion was commenced 15 minutes before onset of the 30-minute coronary occlusion. The infusion was terminated 10 minutes before the occlusion to allow sufficient time for drug washout. The following four agonists were used: 0.55 mmol/L ACh and, in µmol/L, bradykinin 0.4, morphine 0.3, and phenylephrine 0.1. Additional groups of rabbit hearts were similarly treated with these agonists and were simultaneously treated with one of two antagonists, either 5-HD (200 µmol/L), which is a mitochondrial KATP channel closer, or MPG (300 µmol/L), which is a free radical scavenger. The antagonists were administered to bracket the agonist infusion and, therefore, were present in the perfusate from 5 minutes before to 5 minutes after the agonist infusion. Doses of agonists selected were those known to precondition hearts, and doses of antagonists were those known to block preconditioning. Additionally, three other groups of hearts were studied. Groups of hearts were treated simultaneously with the agonist PIA (1 µmol/L) and either MPG or 5-HD as detailed above and also with adenosine (100 µmol/L) and 5-HD.
Measurement of Infarct and Risk Zones
At the end of the experiment, the coronary artery was reoccluded and the heart was perfused with saline containing 1 to 10 µmol/L fluorescent microspheres (Duke Scientific Co) to delineate the area at risk as the nonfluorescent region. Hearts were frozen, cut into 2-mm transverse slices, incubated for 20 minutes in 1% triphenyltetrazolium chloride in 100 mmol/L phosphate buffer (pH 7.4, 37°C), and immersed in 10% formalin to stain viable myocardium red. The borders between fluorescent and nonfluorescent regions were marked under ultraviolet light to identify the risk zone. Areas of risk zone and infarction were planimetered, and volumes calculated by multiplying by slice thickness. Infarct size is presented as a percentage of the risk zone.
Chemicals
Phenylephrine, adenosine, PIA, bradykinin, ACh, MPG, and 5-HD were obtained from Sigma. Morphine sulfate was purchased from Bergen Brunswig. All drugs were dissolved in 0.9% saline and diluted in Krebs-Henseleit buffer. Because an aqueous solution of MPG is acidic, the pH was adjusted to 7.35 to 7.45 by addition of 4N sodium hydroxide.
Statistics
All data are presented as mean±SEM. One-way ANOVA combined with Scheffé post hoc test was used to test for differences in baseline hemodynamics and infarct size between groups. The significance of a shift in the relationship of infarct size plotted against risk zone volume for studies involving an agonist and the two antagonist agents 5-HD and MPG was determined by ANCOVA. ANOVA with replication was used to test for temporal differences in hemodynamics in any given group. The difference was considered significant if the P value was <0.05.
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Results |
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Heart rate, left ventricular developed pressure, and coronary flow at baseline, immediately before coronary occlusion, at the end of the occlusion period, and after 1 hour of reperfusion are summarized in Table 1. There were no significant differences between groups at baseline. Brief infusions of vasoactive agonists transiently influenced these hemodynamic parameters. However, in virtually all cases hemodynamic variables had returned to baseline values by the onset of the coronary occlusion. The exceptions were small decreases in developed pressure and/or heart rate in hearts treated with PIA or adenosine. Developed pressure and coronary flow decreased during coronary occlusion with partial recovery during reperfusion.
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Infarct data are presented in Table 2. Average risk zone size ranged from 0.68 to 1.12 cm3, although there was no difference among all groups studied. More importantly, when only the groups of specific agonist and agonist combined with either 5-HD or MPG were evaluated, no differences in risk zone size were observed. In untreated control hearts infarct size averaged 29.1±2.8% of the risk zone (Figure 1). ACh resulted in significant salvage, and infarction was only 9.2±2.7% of the risk zone (P<0.05 versus control). Consistent with the data of Yao et al,4 ACh protection was abrogated by either MPG (35.2±3.9%) or 5-HD (27.8±2.4%) (Figure 1). When infarct size was plotted against risk zone volume for all experiments, the regression line for the ACh data was significantly different from those for the two groups treated simultaneously with either MPG or 5-HD (data not shown).
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As expected from prior experience, bradykinin (Figure 2), morphine (Figure 3), and phenylephrine (Figure 4) were all protective. Each of these agonists significantly reduced infarction (P<0.05 versus control). This protection by each agonist was consistently aborted by both MPG and 5-HD (Figures 2 through 4). Again, the regression line for the data from hearts treated with only the agonist was significantly different from those for combined treatment with either MPG or 5HD (data not shown).
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The effects of MPG and 5-HD on the preconditioning effect of the adenosine analog PIA11 are demonstrated in Figure 5. In contrast to the blockade of the infarct-sparing effects of bradykinin, morphine, and phenylephrine, neither MPG nor 5-HD affected the protective action of PIA. Because of these unexpected findings, we also determined the effect of 5-HD on protection by adenosine (Figure 5). As with PIA, 5-HD had no effect on the salutary action of adenosine. When infarct size was plotted against risk zone volume, all regression lines for PIA and adenosine groups were significantly different from that for the control group (data not shown).
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Discussion |
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Many agonists trigger preconditioning in the heart. Some, such as adenosine, bradykinin, and opioids, are known to exit from ischemic myocardium in sufficient amounts to play significant trigger roles in ischemic preconditioning.2 Other agonists can also trigger preconditioning when administered exogenously, but are not produced in sufficient concentrations in the rabbit heart (eg, ACh and catecholamines) to play a role in endogenous preconditioning.2 Despite this distinction, it was previously believed that all of these agonists triggered protection by activating Gi proteins, which in turn stimulated phospholipase enzymes resulting in PKC activation and initiation of a kinase cascade. However, the data presented above suggest that this paradigm must be altered. All agonists are not equivalent.
ACh, bradykinin, opioids, and phenylephrine appear to have much in common. All four agonists are capable of sparing ischemic myocardium, and that protection involves both free radicals and mitochondrial KATP channels. It is notable that free radicals are no longer considered to be solely detrimental effectors in ischemic and reperfused myocardium, but are now being proposed to have roles as critical intracellular messengers. In these experiments as well as those in prior reports,8,9 free radicals have been observed to trigger acute preconditioning. Free radicals are also responsible for the protective effect of late or second-window preconditioning against stunning12 as well as the late preconditioning effect of NO donors against both stunning and infarction.13 Hence, free radical production can now also be considered to have a salutary role in ischemic tissue.
The work of Yao et al4 in isolated chick cardiomyocytes has already shown that ACh can cause these cells to produce a burst of free radicals that can be markedly attenuated by either a free radical scavenger, interference with electron transport in the mitochondria, or closure of mitochondrial KATP channels. These observations cannot uncover whether it is opening of the KATP channels or free radical production that is upstream, and furthermore they do not indicate how ACh might interact with the mitochondria. However, additional support for an interaction between free radicals and KATP channels in cardioprotection is found in a study by Forbes et al.14 In isolated rat hearts, recovery of left ventricular function after ischemia/reperfusion was materially improved if the hearts had been treated with diazoxide, an opener of mitochondrial KATP channels. This protection was blocked by the antioxidant N-acetylcysteine. We, too, have observed that the ability of diazoxide to trigger protection in isolated rabbit hearts is aborted by the two free radical scavengers MPG and Mn(III)tetrakis(4-benzoic acid) porphyrin chloride.3
ACh and adenosine receptors are felt to be coupled to the same G protein, Gi.15 As a result, ACh and adenosine have almost indistinguishable effects on the heart. Therefore, we assumed that adenosine would mimic ACh in the above protocol. We were very surprised when the protective action of neither adenosine nor PIA was affected by MPG or 5-HD. Therefore, in contrast to the other agonists examined, the triggering action of adenosine is not dependent on either free radicals or mitochondrial KATP channels. The most likely explanation is that adenosine results in direct activation of the kinases. The role of PKC in preconditioning is now well established. Ample evidence also indicates that at least one tyrosine kinase is involved.16,17 We18–20 and others16,21 have proposed that the p38 MAPK cascade is the site of the tyrosine kinase, although that remains controversial.22–25
In prior studies from Gross’s laboratory, the protective effects of adenosine in an open-chest canine model were blocked by either glibenclamide26,27 or 5-HD.27 Furthermore, Miura et al28 demonstrated in an isolated rabbit heart model that 5-HD prevented the infarct-sparing effect of the adenosine analog PIA. However, in all three of these studies the KATP channel blockers were present during the trigger as well as mediator phase of the preconditioning protocol. Therefore, one cannot be certain that glibenclamide or 5-HD was indeed preventing the ability of adenosine to trigger preconditioning or having a blocking effect during the index ischemia. In the present study, we have examined only the trigger phase, because 5-HD was washed out before ischemia. In a prior study from this laboratory, the adequacy of washout of 5-HD in a similar protocol was confirmed.3 Furthermore, because 5-HD failed to block the protective action of adenosine, our conclusion would be the same even if 5-HD had not been completely washed out before the index ischemia. Therefore, we can conclude that the triggering effect of adenosine is not abrogated by either a KATP channel blocker or a free radical scavenger.
A new paradigm based on the presented data is shown in Figure 6. In this scheme PKC and p38 MAPK are in parallel, because both can be directly activated by free radicals. The concept of two parallel pathways also accounts for the inability of either PKC or tyrosine kinase blockade, each of which can block protection from one preconditioning cycle,17,29 to abort protection triggered by multiple preconditioning cycles, whereas their combination could.30–32 Not only is the pathway highly redundant at the receptor and kinase levels, but now even the pathways between the receptors and the kinases appear to contain redundancy.
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, and A1, bradykinin, opioid, and adenosine receptor subtypes, respectively; and 
, ß, and 
, subunits of Gi protein. |
Acknowledgments |
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This study was supported in part by the National Heart, Lung, and Blood Institute of the NIH (Grants HL-20648 and HL-50688). G.H. was on sabbatical leave from the University of Essen and was supported by the Volkswagen-Stiftung.
Received May 7, 2001; accepted June 8, 2001.
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A. D. T. Costa, C. L. Quinlan, A. Andrukhiv, I. C. West, M. Jaburek, and K. D. Garlid The direct physiological effects of mitoKATP opening on heart mitochondria Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H406 - H415. [Abstract] [Full Text] [PDF]
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 J. Frassdorf, N. C. Weber, D. Obal, O. Toma, J. Mullenheim, G. Kojda, B. Preckel, and W. Schlack Morphine Induces Late Cardioprotection in Rat Hearts In Vivo: The Involvement of Opioid Receptors and Nuclear Transcription Factor {kappa}B Anesth. Analg., October 1, 2005; 101(4): 934 - 941. [Abstract] [Full Text] [PDF]
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C. E. Darling, R. Jiang, M. Maynard, P. Whittaker, J. Vinten-Johansen, and K. Przyklenk Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2 Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1618 - H1626. [Abstract] [Full Text] [PDF]
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 L. Button, S. E Mireylees, R. Germack, and J. M Dickenson Phosphatidylinositol 3-kinase and ERK1/2 are not involved in adenosine A1, A2A or A3 receptor-mediated preconditioning in rat ventricle strips Exp Physiol, September 1, 2005; 90(5): 747 - 754. [Abstract] [Full Text] [PDF]
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T. Okada, H. Otani, Y. Wu, T. Uchiyama, S. Kyoi, R. Hattori, T. Sumida, H. Fujiwara, and H. Imamura Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H761 - H767. [Abstract] [Full Text] [PDF]
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 Z.-K. Wu, S. Vikman, J. Laurikka, E. Pehkonen, T. Iivainen, H. V. Huikuri, and M. R. Tarkka Nonlinear heart rate variability in CABG patients and the preconditioning effect Eur. J. Cardiothorac. Surg., July 1, 2005; 28(1): 109 - 113. [Abstract] [Full Text] [PDF]
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 S. Kimura, G.-X. Zhang, A. Nishiyama, T. Shokoji, L. Yao, Y.-Y. Fan, M. Rahman, T. Suzuki, H. Maeta, and Y. Abe Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II Hypertension, May 1, 2005; 45(5): 860 - 866. [Abstract] [Full Text] [PDF]
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R. P. Brandes Triggering Mitochondrial Radical Release: A New Function for NADPH Oxidases Hypertension, May 1, 2005; 45(5): 847 - 848. [Full Text] [PDF]
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 D. A Brown, J. M Lynch, C. J Armstrong, N. M Caruso, L. B Ehlers, M. S Johnson, and R. L Moore Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat J. Physiol., April 15, 2005; 564(2): 619 - 630. [Abstract] [Full Text] [PDF]
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T. Krieg, S. Philipp, L. Cui, W. R. Dostmann, J. M. Downey, and M. V. Cohen Peptide blockers of PKG inhibit ROS generation by acetylcholine and bradykinin in cardiomyocytes but fail to block protection in the whole heart Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1976 - H1981. [Abstract] [Full Text] [PDF]
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D. A. Liem, M. te Lintel Hekkert, O. C. Manintveld, F. Boomsma, P. D. Verdouw, and D. J. Duncker Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1165 - H1172. [Abstract] [Full Text] [PDF]
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T. Krieg, Q. Qin, S. Philipp, M. F. Alexeyev, M. V. Cohen, and J. M. Downey Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2606 - H2611. [Abstract] [Full Text] [PDF]
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Q. Qin, X.-M. Yang, L. Cui, S. D. Critz, M. V. Cohen, N. C. Browner, T. M. Lincoln, and J. M. Downey Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H712 - H718. [Abstract] [Full Text] [PDF]
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 P. S. Fischbach, A. White, T. D. Barrett, and B. R. Lucchesi Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 554 - 559. [Abstract] [Full Text] [PDF]
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C.-M. Cao, Q. Xia, J. Tu, M. Chen, S. Wu, and T.-M. Wong Cardioprotection of Interleukin-2 Is Mediated via {kappa}-Opioid Receptors J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 560 - 567. [Abstract] [Full Text] [PDF]
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 D. Hausenloy, A. Wynne, M. Duchen, and D. Yellon Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection Circulation, April 13, 2004; 109(14): 1714 - 1717. [Abstract] [Full Text] [PDF]
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Y. Ichikawa, T. Miura, A. Nakano, T. Miki, Y. Nakamura, K. Tsuchihashi, and K. Shimamoto The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of ischemic preconditioning Cardiovasc Res, April 1, 2004; 62(1): 167 - 175. [Abstract] [Full Text] [PDF]
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 M. O. Gray, H.-Z. Zhou, I. Schafhalter-Zoppoth, P. Zhu, D. Mochly-Rosen, and R. O. Messing Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase C{epsilon} J. Biol. Chem., January 30, 2004; 279(5): 3596 - 3604. [Abstract] [Full Text] [PDF]
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O. Oldenburg, Q. Qin, T. Krieg, X.-M. Yang, S. Philipp, S. D. Critz, M. V. Cohen, and J. M. Downey Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H468 - H476. [Abstract] [Full Text] [PDF]
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K. Kuzume, R. A. Wolff, K. Amakawa, K. Kuzume, and D. M. Van Winkle Sustained exogenous administration of Met5-enkephalin protects against infarction in vivo Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2463 - H2470. [Abstract] [Full Text] [PDF]
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J. P. Headrick, B. Hack, and K. J. Ashton Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1797 - H1818. [Abstract] [Full Text] [PDF]
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M. Zaugg, E. Lucchinetti, M. Uecker, T. Pasch, and M. C. Schaub Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms Br. J. Anaesth., October 1, 2003; 91(4): 551 - 565. [Abstract] [Full Text] [PDF]
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 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
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 S. Ghosh and M. Galinanes Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 133 - 142. [Abstract] [Full Text] [PDF]
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J. P Headrick, L. Willems, K. J Ashton, K. Holmgren, J. Peart, and G P. Matherne Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression J. Physiol., June 15, 2003; 549(3): 823 - 833. [Abstract] [Full Text] [PDF]
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T. C. Zhao and R. C. Kukreja Protein kinase C-{delta} mediates adenosine A3 receptor-induced delayed cardioprotection in mouse Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H434 - H441. [Abstract] [Full Text] [PDF]
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J. N. Peart and G. J. Gross Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H81 - H89. [Abstract] [Full Text] [PDF]
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J. Peart and J. P Headrick Adenosine-mediated early preconditioning in mouse: protective signaling and concentration dependent effects Cardiovasc Res, June 1, 2003; 58(3): 589 - 601. [Abstract] [Full Text] [PDF]
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T. Krieg, M. Landsberger, M. F. Alexeyev, S. B. Felix, M. V. Cohen, and J. M. Downey Activation of Akt is essential for acetylcholine to trigger generation of oxygen free radicals Cardiovasc Res, April 1, 2003; 58(1): 196 - 202. [Abstract] [Full Text] [PDF]
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 J. G. Bovill Anesthesia for Patients with Impaired Ventricular Function Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2003; 7(1): 49 - 54. [PDF]
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L. G. Kevin, M. M. Sayin, O. Ozatamer, and N. U:nal Propofol and myocardial lipid peroxidation Br. J. Anaesth., February 1, 2003; 90(2): 253 - 254. [Full Text] [PDF]
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J. Peart, L. Willems, and J. P. Headrick Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H519 - H527. [Abstract] [Full Text] [PDF]
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A. Skyschally, R. Schulz, P. Gres, H.-G. Korth, and G. Heusch Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H698 - H703. [Abstract] [Full Text] [PDF]
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Q. Qin, J. M. Downey, and M. V. Cohen Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H727 - H734. [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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A. Yvon, J.-L. Hanouz, X. Terrien, P. Ducouret, R. Rouet, H. Bricard, and J.-L. Gerard Electrophysiological effects of morphine in an in vitro model of the 'border zone' between normal and ischaemic-reperfused guinea-pig myocardium Br. J. Anaesth., December 1, 2002; 89(6): 888 - 895. [Abstract] [Full Text] [PDF]
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T. Krieg, Q. Qin, E. C. McIntosh, M. V. Cohen, and J. M. Downey ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2322 - H2330. [Abstract] [Full Text] [PDF]
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E. Kodani, Y.-T. Xuan, K. Shinmura, H. Takano, X.-L. Tang, and R. Bolli delta -Opioid receptor-induced late preconditioning is mediated by cyclooxygenase-2 in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1943 - H1957. [Abstract] [Full Text] [PDF]
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 A. Tsuchida, T. Miura, M. Tanno, J. Sakamoto, T. Miki, A. Kuno, T. Matsumoto, Y. Ohnuma, Y. Ichikawa, and K. Shimamoto Infarct size limitation by nicorandil: Roles of mitochondrial KATP channels, sarcolemmal KATP channels, and protein kinase C J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1523 - 1530. [Abstract] [Full Text] [PDF]
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L. M. Schwartz, T. S. Welch, and M. S. Crago Cardioprotection by multiple preconditioning cycles does not require mitochondrial KATP channels in pigs Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1538 - H1544. [Abstract] [Full Text] [PDF]
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O. Oldenburg, M. V Cohen, D. M Yellon, and J. M Downey Mitochondrial KATP channels: role in cardioprotection Cardiovasc Res, August 15, 2002; 55(3): 429 - 437. [Abstract] [Full Text] [PDF]
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D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
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G.F Baxter Role of adenosine in delayed preconditioning of myocardium Cardiovasc Res, August 15, 2002; 55(3): 483 - 494. [Abstract] [Full Text] [PDF]
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O. Oldenburg, Q. Qin, A. R Sharma, M. V Cohen, J. M Downey, and J. N Benoit Acetylcholine leads to free radical production dependent on KATP channels, Gi proteins, phosphatidylinositol 3-kinase and tyrosine kinase Cardiovasc Res, August 15, 2002; 55(3): 544 - 552. [Abstract] [Full Text] [PDF]
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R. M Smith, N. Suleman, J. McCarthy, and M. N Sack Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNF{alpha} gene Cardiovasc Res, August 15, 2002; 55(3): 553 - 560. [Abstract] [Full Text] [PDF]
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S. Wolfrum, K. Schneider, M. Heidbreder, J. Nienstedt, P. Dominiak, and A. Dendorfer Remote preconditioning protects the heart by activating myocardial PKC{epsilon}-isoform Cardiovasc Res, August 15, 2002; 55(3): 583 - 589. [Abstract] [Full Text] [PDF]
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Y. Yue, Q. Qin, M. V Cohen, J. M Downey, and S. D Critz The relative order of mKATP channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart Cardiovasc Res, August 15, 2002; 55(3): 681 - 689. [Abstract] [Full Text] [PDF]
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D. A. Liem, P. D. Verdouw, H. Ploeg, S. Kazim, and D. J. Duncker Sites of action of adenosine in interorgan preconditioning of the heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H29 - H37. [Abstract] [Full Text] [PDF]
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G. J. Gross and D. C. Warltier Prologue: nonclassical modalities of myocardial preconditioning Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H1951 - H1952. [Full Text] [PDF]
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H. Y. Zhang, B. C. McPherson, H. Liu, T. S. Baman, P. Rock, and Z. Yao H2O2 opens mitochondrial KATP channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1395 - H1403. [Abstract] [Full Text] [PDF]
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P. Eaton, H. L. Byers, N. Leeds, M. A. Ward, and M. J. Shattock Detection, Quantitation, Purification, and Identification of Cardiac Proteins S-Thiolated during Ischemia and Reperfusion J. Biol. Chem., March 15, 2002; 277(12): 9806 - 9811. [Abstract] [Full Text] [PDF]
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