© 1995 American Heart Association, Inc.
Articles |
Does Ischemic Preconditioning in the Human Involve Protein Kinase C and the ATP-Dependent K+ Channel?
Studies of Contractile Function After Simulated Ischemia in an Atrial In Vitro Model
From the Hatter Institute (M.E.S.-D., D.M.Y.), Department of Academic and Clinical Cardiology, University College London (UK) Hospitals, and Bristol-Myers Squibb Pharmaceuticals Research Institute (G.J.G.), Princeton, NJ.
Correspondence to Prof D.M. Yellon, The Hatter Institute, Department of Academic and Clinical Cardiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK.
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Abstract |
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Abstract Protein kinase C (PKC) and the ATP-dependent K+ channel (KATP channel) have been implicated in the mechanism of ischemic preconditioning in animal models. This study investigated the role of KATP channels and PKC in preconditioning in human myocardium and whether KATP channels are activated via a PKC-dependent pathway. Right atrial trabeculae were superfused with Tyrode’s solution and paced at 1 Hz. After stabilization, muscles underwent one of nine different protocols, followed by simulated ischemia (SI) consisting of 90 minutes of hypoxic substrate-free superfusion paced at 3 Hz and then by 120 minutes of reperfusion. Preconditioning consisted of 3 minutes of SI and 7 minutes of reperfusion. The experimental end point was recovery of contractile function after SI, presented here as percentage recovery (%Rec) of baseline function. %Rec was significantly improved by preconditioning by the KATP channel opener cromakalim (CK), and by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) compared with nonpreconditioned controls when these treatments were given before the SI insult (control group, 29.5±3.6%; preconditioned group, 63.5±5.4%, CK-treated group, 52.9±3.1%; and DOG-treated group, 48.0±3.5%; P<.01). The effects of CK could be blocked by the KATP channel blocker glibenclamide (%Rec, 17.8±3.5%). Preconditioning could be blocked by the PKC antagonist chelerythrine (%Rec, 24.1±5.0%) and the KATP blocker glibenclamide (%Rec, 24.8±3.1%). The effects of DOG could also be blocked by glibenclamide (%Rec, 23.1±2.3%). These findings show that protection against contractile dysfunction after SI can be induced by activation of PKC and by the opening of the KATP channel and that the protection induced by PKC activation and preconditioning can be blocked by blocking the KATP channel. This suggests that the mechanism of preconditioning in humans may act via PKC and rely on the action of the KATP channel as the end effector.
Key Words: protein kinase C • ATP-dependent K+ channel • ischemic preconditioning • human atrium • contractile function
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A brief period of ischemia followed by reperfusion renders the heart more resistant to injury from a subsequent longer ischemic insult instead of accentuating the injury.1 This endogenous and highly protective phenomenon is known as ischemic preconditioning. Although ischemic preconditioning is now established in a variety of mammalian models, there is only limited evidence that the effect can also be induced in humans.
Evidence that preconditioning occurs in humans comes partly from studies during therapeutic PTCA. These studies show that the severity of myocardial ischemia is less during repeat balloon inflations than during the first inflation and are thought to demonstrate a preconditioning effect.2 3 4 However, these studies must be interpreted with caution because of the short periods of ischemia involved (<2 minutes) and the confounding effect of the possible opening up of collateral vessels. Other studies in humans have retrospectively examined whether a period of angina 24 to 48 hours before an acute myocardial infarction confers a protective effect,5 6 and these also lend support to the theory that preconditioning occurs in humans. The only in vivo prospective study using a model of global ischemia to investigate preconditioning in humans is that of Yellon et al,7 who examined whether a preconditioning protocol before cross-clamp fibrillation during coronary artery bypass surgery protects the myocardium from prolonged ischemia. Their study showed that preconditioning ultimately leads to a preservation of ATP levels in preconditioned human hearts in contrast to nonpreconditioned hearts. These findings are in keeping with the metabolic changes seen in animal models8 and add weight to the theory that preconditioning does occur in humans.
The mechanism of preconditioning is incompletely understood. The most favored current hypothesis for preconditioning suggests that endogenous ligands such as adenosine initiate an intracellular pathway by acting on G protein–linked receptors, which leads to the activation of PKC via diacylglycerol.9 Activated PKC then phosphorylates a secondary effector protein, which is thought to induce protection.
There is some evidence in humans that adenosine is the endogenous mediator of protection,10 but there is no evidence as yet that PKC is involved in human preconditioning, despite much evidence that PKC is essential in several animal models of preconditioning.9 11 12 The role of PKC is not entirely certain, and there is some conflicting evidence in a pig model that inhibition of PKC may be beneficial.13 It seems likely that the end-effector protein in the hypothesis described above induces myocardial protection by slowing cell metabolism and thus reducing ATP consumption.14 This would lead to the preservation of cells during a prolonged period of ischemia. It has been suggested that the KATP channel may be this end effector, since the opening of these channels causes an influx of K+ that shortens the cardiac action potential and limits ATP depletion and Ca2+ influx, and there is much support for this theory (eg, Auchampach et al15 and Gross and Auchampach16 ). There is experimental evidence in favor of the KATP channel being involved in preconditioning in larger mammals such as the pig17 and the dog,15 16 but the evidence in smaller animal models is less convincing, with both positive and negative studies in the rabbit18 19 and negative studies in the rat.20 21 A recent clinical study in humans involving PTCA22 found that blockade of the KATP channel with GB prevented the preconditioning effect normally seen in this angioplasty model during repeat balloon inflation, suggesting that the KATP channel may also be important in preconditioning in humans.
The aims of the present study were to investigate whether PKC plays a central role in preconditioning in human myocardium and whether the opening of the KATP channel is essential for preconditioning to occur. This study also set out to test the hypothesis that the KATP channel may be the end effector in humans by investigating whether this channel is activated via a PKC-dependent pathway. We examined isolated, superfused, and contracting right atrial trabeculae and measured differences in contractile recovery after SI. The roles of PKC and the KATP channel were investigated pharmacologically.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental Methods
Experiments were performed on trabeculae derived from human atrium. Specimens of right atrial appendage were obtained from the right atrial cannula insertion site in patients undergoing cardiac bypass before coronary artery surgery. All subjects had chronic stable angina. Patients were excluded if they had atrial arrhythmias or right ventricular failure or were taking antiarrhythmic drugs or oral hypoglycemic agents (for diabetes mellitus). Prior ethical approval had been obtained from the Middlesex Hospital Clinical Investigations Panel. The specimens were kept oxygenated in modified Tyrode’s solution at 4°C. A single atrial trabecula (diameter,
0.9 mm; length, 
3
mm) was identified under magnification, tied at one end with a 7/0 silk
suture, and then dissected out with a small wedge of atrial wall at the
free end. The silk suture was used to attach one end of the
trabecula to a fixed post in an organ bath, and the other
end was attached to a force transducer (Gould Statham UCT2) by snaring
the wedge of atrial wall. The muscles were suspended horizontally in
the organ bath through which there was a continuous flow of
superfusate oxygenated with a 95%
O2/5% CO2 gas mixture. The organ bath
was covered to prevent gas exchange with the atmosphere. The
PO2,
PCO2, and pH in the organ bath were
monitored by intermittent analyses of the effluent by using an
automated blood gas analyzer (model AVL 993, AVL Medical
Instruments). The pH was kept between 7.35 and 7.45, and the
temperature, monitored by a thermocouple in the bath, was maintained at
37°C. Flow through the bath was maintained at 8 mL/min. During the
SI, the superfusate was free of substrate and was bubbled
with 95% N2/5% CO2 (pH 7.24 to 7.34)
so that it was hypoxic. Once suspended, trabeculae were paced by field stimulation at 1 Hz. The platinum pacing electrodes were positioned within the bath on either side of the trabecula, and pacing was driven by an isolated stimulator (Digitimer DS2) triggered by a computerized clock. The pulse width was fixed at 5 ms, and the pulse amplitude was set at twice threshold (6 to 8 V). The output of the force transducer was recorded on paper (Gould RS3400 chart recorder). The width and length of specimens were measured at the end of the experiment with an eyepiece graticule in an overhead microscope (Prior), and all specimens were then weighed.
Materials
The Tyrode’s solution consisted of (mmol/L) NaCl 118.5, KCl
4.8, NaHCO3 24.8, KH2PO4 1.2,
MgSO4 · 7H2O 1.44,
CaCl2 · 2H2O 1.8, glucose 10.0, and pyruvic
acid 10.0. In the substrate-free Tyrode’s solution, choline
chloride (7 mmol/L) was substituted for glucose and pyruvic acid to
maintain constant osmolarity. All reagents were Analar grade (BDH
Chemicals) except for the pyruvic acid (Sigma Chemical Co). The
selective PKC blocker CHE (LC Laboratories) was dissolved in distilled
water and added to the Tyrode’s solution to give a 10 µmol solution.
The diacylglycerol analogue DOG (Sigma), a selective PKC
activator, was initially dissolved in dimethyl sulfoxide
(10 mg in 200 µL), and this was added to the Tyrode’s solution to
give a final concentration of 30 µmol. The KATP channel
opener CK was dissolved in dimethyl sulfoxide initially (5.16 mg in 200
µL) and then added to the Tyrode’s solution to give a final
concentration of 30 µmol. The KATP channel blocker GB was
made up to a concentration of 1 µmol in 100 mL Tyrode’s
solution.
Experimental Protocols
Trabeculae were suspended in the bath and paced
unstretched for 30 minutes. They were then gradually stretched in a
stepwise manner for 
15 minutes until the maximum force of
contraction was achieved. All muscles were then allowed to equilibrate
for at least 45 minutes. All groups eventually underwent a period of SI
followed by reperfusion, which consisted of 90 minutes of hypoxic
substrate-free superfusion and rapid pacing (3 Hz) followed by
reperfusion for 120 minutes with normal Tyrode’s solution and pacing
at 1 Hz. The preconditioning protocol consisted of 3 minutes of hypoxic
substrate-free superfusion with rapid pacing at 3 Hz followed by
reperfusion with oxygenated normal Tyrode’s solution and
pacing at 1 Hz. Samples were used for one protocol only. Fig 1
shows the experimental protocols for the nine groups:
(1) control group, stabilization period then SI (n=6); (2) PC group,
preconditioning protocol then SI (n=6); (3) C+DOG group, 10 minutes of
superfusion with DOG (30 µmol) before SI (n=6); (4) PC+CHE group,
protocol as for the PC group with CHE (10 µmol) present during
the 7-minute reperfusion period (n=6). (5) CK group, 5 minutes of
superfusion with CK (30 µmol) and 7-minute washout before SI (n=6);
(6) CK+GB group, protocol as for CK group with GB (1 µmol)
present from 10 minutes before the administration of CK until SI
(n=4); (7) PC+GB group, protocol as for PC group with GB (1 µmol)
present from 10 minutes before the preconditioning protocol until
SI (n=4); (8) C+GB group, 10 minutes of GB (1 µmol) before SI (n=4);
and (9) DOG+GB group, 10 minutes of superfusion with DOG (30 µmol)
before SI with GB (1 µmol) present from 20 minutes before SI
(n=5).
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Statistical Analysis
Data are expressed as group mean±SEM. Statistical differences
between groups were evaluated by one-way ANOVA with Fisher’s
protected least-significant difference post hoc
test.23 A value of P.01 was considered
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Samples were obtained from patients with stable ischemic heart disease (40 men and 7 women; age range, 36 to 80 years; mean age, 62 years). There were no exclusions in this study; all samples completed the protocol to which they were randomly assigned. There were 47 patients in total, and each of the 47 experimental samples came from a different patient and underwent one protocol only. Baseline characteristics including resting force and peak developed force were similar in all groups (see Table 1
); therefore,
experimental data on developed force are presented graphically
as a percentage of baseline developed force.
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Figs 2 and 3 show the results for
developed force as a percentage of baseline. Time 0 indicates the
beginning of SI; therefore, reperfusion with oxygenated
Tyrode’s solution extends from 90 to 210 minutes. As shown in the
diagram of the protocols (see Fig 1
), SI is preceded in all groups by a
stabilization period and various pretreatments (indicated on the graphs
by drug/preconditioning). As noted above, there was no significant
difference in developed force between the nine groups at the end of the
stabilization period, and this baseline function is denoted as 100%
developed force. Both graphs include the data for the control and PC
groups for comparison.
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Fig 2 illustrates the results for those groups specifically relevant to
the investigation of the KATP channel. The preconditioning
protocol caused a significant reduction in developed force to
41.8±10.5% in the PC group, which recovered to baseline before
entering SI. A similar reduction in function occurred in the PC+GB
group, which also returned to baseline before SI. CK treatment caused a
significant reduction in function in the CK and CK+GB groups (see Fig 2). Reperfusion before the long hypoxia in these groups did not
result in the full recovery of developed force to baseline values,
although the CK+GB group did partially recover (47.1±13.1%). There
was no difference in function between groups during the 90-minute
period of hypoxia. On reperfusion with oxygenated
Tyrode’s solution, there was significantly greater recovery of
function in the PC and CK groups compared with the control group
(control, 29.5±3.6%; PC, 63.5±5.4%; and CK, 52.9±3.1%;
P<.01). Recovery in the PC group was not significantly
different from that in the CK group. There was no difference between
control and the other groups (CK+GB, 17.8±3.5%; PC+GB, 24.8±3.1%;
and C+GB, 29.7±3.8%), which all recovered poorly. GB appears to have
no independent detrimental effect on atrial tissue, since recovery of
function in the C+GB group was the same as in group C.
Fig 3 includes the data for the experimental groups specifically
relevant to the investigation of the role of PKC. The PC+CHE group
underwent a reduction in function similar to that in the PC group
during the preconditioning protocol. The addition of DOG (C+DOG group)
caused some reduction in function before SI, but this was not
significantly different from the control group. On reperfusion, there
was a significantly greater percentage of functional recovery in the
C+DOG group (48.0±3.5%), which was similar to the recovery seen in
the PC and CK groups (see Fig 2). The PC+CHE group had the same poor
functional recovery as the control group (PC+CHE, 24.1±5.0%; control,
29.5±3.6%). Finally, in the DOG+GB group, where the KATP
channel blocker GB was given in addition to DOG, the protective effect
of DOG was lost, and this group had the same recovery as the control
group (DOG+GB, 23.1±2.3%; control, 29.5±3.6%).
Table 2 shows the data for time to onset of contracture,
defined as the time from the onset of the 90-minute hypoxia to
an increase of 0.05 g in resting force above baseline, and time to peak
contracture, defined as the time taken for the baseline force to rise
to maximum. There was no significant difference between the
experimental groups and the control group for either the time to onset
of contracture or time to peak contracture.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study confirms that human atrium can be protected from an ischemic insult by activation of the KATP channel with CK. The protection brought about by both preconditioning and CK can be blocked by the KATP channel blocker GB, suggesting that the protection of preconditioning may result from KATP channel opening.
Activation of PKC with the diacylglycerol analogue DOG results in a degree of myocardial protection similar to that seen with preconditioning or treatment with CK (P<.01); therefore, it seems likely that the mechanism of preconditioning in humans involves a PKC-dependent pathway, in keeping with the majority of evidence from other species.9 11 In addition, the finding that the protective effect of activating PKC with DOG is abolished by blocking the KATP channel with GB suggests that the KATP channel may be activated via PKC and that this channel may be the end effector in the mechanism of preconditioning in humans. CK treatment resulted in a decrease in developed force before the 90-minute SI insult. However, the protective action of CK is unlikely to be due to cardioplegia, because GB abolished the protective effect of treatment with CK but not the preischemic cardiodepression that it caused.
The present study is the first to provide direct evidence that the KATP channel is involved in preconditioning in human myocardium. The first study to demonstrate a possible role for this channel in preconditioning in humans was that of Tomai et al,22 who used a clinical angioplasty model. Their evidence is indirect but highly persuasive. They showed that ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with GB, suggesting that preconditioning is mediated by KATP channels in humans. There are several clinical studies suggesting that preconditioning occurs in humans,2 3 4 5 6 7 but as yet, the only direct evidence that we have comes from two in vitro studies. The study of Ikonomidis et al24 used human ventricular cardiomyocyte cell cultures; they were able to show that these isolated myocytes could be protected against a 90-minute period of SI by a preconditioning protocol. The other study providing direct evidence comes from our own department10 and uses the same model as the present study. We were able to show that human atrial trabeculae that had been preconditioned had a significantly better postischemic recovery of contractile function than nonpreconditioned trabeculae. Importantly, this study also demonstrated that adenosine was involved in human preconditioning, since we were able to show that an adenosine agonist, 8-p-sulfophenyltheophylline, was able to induce the same degree of protection against ischemia as preconditioning, providing the first evidence in favor of adenosine being the endogenous ligand that "switches on" preconditioning in humans.
The present study used isolated human atrial trabeculae in an attempt to examine the mechanism of preconditioning in human myocardium. The advantages of an isolated human preparation are that one can avoid the problem of variable collateral flow experienced with in vivo models and that there are no ethical considerations involved in the use of experimental drugs in vitro. Atrial tissue was chosen because it was available and because sampling was part of the routine procedure for coronary artery bypass grafting. Atrial specimens make stable preparations and are generally disease free. There are differences between atrial and ventricular tissue, and results from one may not be applicable to the other; however, early experiments in our laboratory (authors’ unpublished data, 1995) suggest that an identical preconditioning effect can be induced in ventricular tissue if a shorter ischemic insult is used (60 minutes instead of 90 minutes). Adenosine receptors are present in both atrium and ventricle,25 as are KATP channels,26 although there may be differences in the density of these receptors. For example, Tung et al27 have shown in the guinea pig that the density of KATP channels is significantly lower in atrial than ventricular tissue. In view of these similarities in both the response to experimental ischemia and the presence of relevant channels and receptors, it seems probable that human atrial and ventricular tissue will respond in a similar way to ischemic preconditioning.
Rather than the "true" ischemia of classic preconditioning, the present study used a period of hypoxic superfusion in combination with rapid pacing to simulate ischemia, and there is a great deal of evidence in animal models of both regional and global hypoxia and in cell culture that hypoxia is as effective as ischemia in inducing preconditioning.28 29 30 31 We know that preconditioning causes improved recovery of contractile function as well as reduced infarct size. For example, a recent in vitro study by Jenkins et al,32 who measured both infarct volume and functional recovery after ischemia, showed that the improved recovery of global left ventricular function produced by preconditioning is proportional to a reduction in infarction, and Cohen et al33 and Przyklenk et al34 were able to correlate improved recovery of systolic shortening with reduced infarct size in in vivo models of regional ischemia. There is no direct evidence in atrial tissue that recovery of global function is proportional to infarct volume, but this is likely to be the case. It is clear from the evidence of these studies that the enhanced recovery of contractile function due to preconditioning, which follows a prolonged period of ischemia, is due to a reduction in infarct size and is not due to a reduction in stunning. Our model uses a 90-minute period of SI as the "ischemic insult," a period much more likely to lead to cell death than stunning, which is induced by shorter periods of 5 to 15 minutes of ischemia. This suggests that our model is indeed one of preconditioning. However, although unlikely, we cannot entirely exclude the possibility that our model involves stunning, and Auchampach et al15 have demonstrated that K+ channel openers are effective in inducing myocardial protection in canine models of both stunning and infarction. In summary, there is evidence that hypoxia can be as effective as ischemia in preconditioning, that recovery of contractile function is a good correlate for the degree of myocyte necrosis, and that this experimental model is one of preconditioning. Therefore, although the findings of the present study strictly relate to hypoxic preconditioning, they should be relevant to ischemic preconditioning also.
In conclusion, the present study demonstrates for the first time that in human myocardium the protective effects of preconditioning can be induced by activation of PKC and the opening of the KATP channel. It also suggests that the KATP channel is activated via PKC, making this channel a likely candidate for the "end effector" in human preconditioning.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr M.E. Speechly-Dick was funded by a Junior Research Fellowship from the British Heart Foundation. Additional funding was provided by The Hatter Foundation.
Received May 17, 1995; accepted July 26, 1995.
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References |
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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]
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C. Penna, G. Alloatti, S. Cappello, D. Gattullo, G. Berta, B. Mognetti, G. Losano, and P. Pagliaro Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2512 - H2520. [Abstract] [Full Text] [PDF]
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A. Crisafulli, F. Melis, F. Tocco, U. M. Santoboni, C. Lai, G. Angioy, L. Lorrai, G. Pittau, A. Concu, and P. Pagliaro Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H235 - H242. [Abstract] [Full Text] [PDF]
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S. D. Solomon, N. S. Anavekar, S. Greaves, J. L. Rouleau, C. Hennekens, M. A. Pfeffer, and HEART Investigators Angina pectoris prior to myocardial infarction protects against subsequent left ventricular remodeling J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1511 - 1514. [Abstract] [Full Text] [PDF]
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T. Miura Myocardial response to ischemic preconditioning: is it a novel predictor of prognosis? J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1004 - 1006. [Full Text] [PDF]
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M. Loubani and M. Galinanes Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: Role of mitochondrial adenosine triphosphate-dependent potassium channels J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 750 - 757. [Abstract] [Full Text] [PDF]
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R. A Kloner, M. T Speakman, and K. Przyklenk Ischemic preconditioning: a plea for rationally targeted clinical trials Cardiovasc Res, August 15, 2002; 55(3): 526 - 533. [Full Text] [PDF]
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L. Samavati, M. M. Monick, S. Sanlioglu, G. R. Buettner, L. W. Oberley, and G. W. Hunninghake Mitochondrial KATP channel openers activate the ERK kinase by an oxidant-dependent mechanism Am J Physiol Cell Physiol, July 1, 2002; 283(1): C273 - C281. [Abstract] [Full Text] [PDF]
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M. Ishihara, I. Inoue, T. Kawagoe, Y. Shimatani, S. Kurisu, K. Nishioka, Y. Kouno, T. Umemura, S. Nakamura, and H. Sato Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1007 - 1011. [Abstract] [Full Text] [PDF]
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J. An, S. G. Varadarajan, E. Novalija, and D. F. Stowe Ischemic and anesthetic preconditioning reduces cytosolic [Ca2+] and improves Ca2+ responses in intact hearts Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1508 - H1523. [Abstract] [Full Text] [PDF]
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M. Loubani and M. Galinanes {{alpha}}1-Adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: Effect of the dose and time of administration J. Thorac. Cardiovasc. Surg., July 1, 2001; 122(1): 103 - 112. [Abstract] [Full Text] [PDF]
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S. Ghosh, N. B. Standen, and M. Galinanes Failure to precondition pathological human myocardium J. Am. Coll. Cardiol., March 1, 2001; 37(3): 711 - 718. [Abstract] [Full Text] [PDF]
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S. P. Bell, M. N. Sack, A. Patel, L. H. Opie, and D. M. Yellon Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2296 - 2302. [Abstract] [Full Text] [PDF]
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D. M. Yellon and A. Dana The Preconditioning Phenomenon : A Tool for the Scientist or a Clinical Reality? Circ. Res., September 29, 2000; 87(7): 543 - 550. [Abstract] [Full Text] [PDF]
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A. E. Saltman, I. B. Krukenkamp, G. R. Gaudette, H. Horimoto, and S. Levitsky Pharmacological preconditioning with the adenosine triphosphate-sensitive potassium channel opener pinacidil Ann. Thorac. Surg., August 1, 2000; 70(2): 595 - 601. [Abstract] [Full Text] [PDF]
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G. R. Gaudette, I. B. Krukenkamp, A. E. Saltman, H. Horimoto, and S. Levitsky Preconditioning with PKC and the ATP-sensitive potassium channels: a codependent relationship Ann. Thorac. Surg., August 1, 2000; 70(2): 602 - 608. [Abstract] [Full Text] [PDF]
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B. J. Pomerantz, T. N. Robinson, T. D. Morrell, J. K. Heimbach, A. Banerjee, and A. H. Harken Selective mitochondrial adenosine triphosphate-sensitive potassium channel activation is sufficient to precondition human myocardium J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 387 - 392. [Abstract] [Full Text] [PDF]
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F. Monti, K. Iwashiro, S. Picard, A. Criniti, S. La Francesca, G. Ruvolo, U. Papalia, P. P. Campa, B. Marino, and P. E. Puddu ADENOSINE TRIPHOSPHATE-DEPENDENT POTASSIUM CHANNEL MODULATION AND CARDIOPLEGIA-INDUCED PROTECTION OF HUMAN ATRIAL MUSCLE IN AN IN VITRO MODEL OF MYOCARDIAL STUNNING J. Thorac. Cardiovasc. Surg., April 1, 2000; 119(4): 842 - 848. [Abstract] [Full Text] [PDF]
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T. L. V. Hoek, L. B. Becker, Z.-H. Shao, C.-Q. Li, and P. T. Schumacker Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion Circ. Res., March 17, 2000; 86(5): 541 - 548. [Abstract] [Full Text] [PDF]
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D. Belhomme, J. Peynet, M. Louzy, J.-M. Launay, M. Kitakaze, and P. Menasche Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery Circulation, November 9, 1999; 100 (2009): II-340 - II-344. [Abstract] [Full Text] [PDF]
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F. G. Spinale Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest Ann. Thorac. Surg., November 1, 1999; 68(5): 1934 - 1941. [Abstract] [Full Text] [PDF]
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L. P. Perrault and P. Menasche Preconditioning: can nature’s shield be raised against surgical ischemic-reperfusion injury? Ann. Thorac. Surg., November 1, 1999; 68(5): 1988 - 1994. [Abstract] [Full Text] [PDF]
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N. Matsuda, K. G. Morgan, and F. W. Sellke PRECONDITIONING IMPROVES CARDIOPLEGIA-RELATED CORONARY MICROVASCULAR SMOOTH MUSCLE HYPERCONTRACTILITY: ROLE OF KATP CHANNELS J. Thorac. Cardiovasc. Surg., September 1, 1999; 118(3): 438 - 445. [Abstract] [Full Text] [PDF]
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F. Tomai, F. Crea, L. Chiariello, and P. A. Gioffre Ischemic Preconditioning in Humans : Models, Mediators, and Clinical Relevance Circulation, August 3, 1999; 100(5): 559 - 563. [Abstract] [Full Text] [PDF]
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J van der Velden, L.J Klein, M van der Bijl, M.A.J.M Huybregts, W Stooker, J Witkop, L Eijsman, C.A Visser, F.C Visser, and G.J.M Stienen Isometric tension development and its calcium sensitivity in skinned myocyte-sized preparations from different regions of the human heart Cardiovasc Res, June 1, 1999; 42(3): 706 - 719. [Abstract] [Full Text] [PDF]
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G. Li, S. Chen, E. Lu, and Y. Li Ischemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients Eur. J. Cardiothorac. Surg., May 1, 1999; 15(5): 653 - 657. [Abstract] [Full Text] [PDF]
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C. P. Baines, G. S. Liu, M. Birincioglu, S. D. Critz, M. V. Cohen, and J. M. Downey Ischemic preconditioning depends on interaction between mitochondrial KATP channels and actin cytoskeleton Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1361 - H1368. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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K.F. Fox, M.R. Cowie, D.A. Wood, A.J.S. Coats, P.A. Poole-Wilson, and G.C. Sutton New perspectives on heart failure due to myocardial ischaemia Eur. Heart J., February 2, 1999; 20(4): 256 - 262. [PDF]
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F. Tomai, A. Danesi, A.S. Ghini, F. Crea, M. Perino, A. Gaspardone, G. Ruggeri, L. Chiariello, and P.A. Gioffre Effects of KATPchannel blockade by glibenclamide on the warm-up phenomenon Eur. Heart J., February 1, 1999; 20(3): 196 - 202. [Abstract] [PDF]
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K. Hu, G.-R. Li, and S. Nattel Adenosine-induced activation of ATP-sensitive K+ channels in excised membrane patches is mediated by PKC Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H488 - H495. [Abstract] [Full Text] [PDF]
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D.J. Patel, H.J. Purcell, and K.M. Fox Cardioprotection by opening of the KATPchannel in unstable angina: Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil Eur. Heart J., January 1, 1999; 20(1): 51 - 57. [Abstract] [PDF]
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S. Kawamura, K.-I. Yoshida, T. Miura, Y. Mizukami, and M. Matsuzaki Ischemic preconditioning translocates PKC-delta and -epsilon , which mediate functional protection in isolated rat heart Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2266 - H2271. [Abstract] [Full Text] [PDF]
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B. Z. Simkhovich, K. Przyklenk, and R. A. Kloner Role of protein kinase C as a cellular mediator of ischemic preconditioning: a critical review Cardiovasc Res, October 1, 1998; 40(1): 9 - 22. [Abstract] [Full Text] [PDF]
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W.R. Tracey, W. Magee, H. Masamune, J. J. Oleynek, and R. J. Hill Selective activation of adenosine A3 receptors with N6-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via KATP channel activation Cardiovasc Res, October 1, 1998; 40(1): 138 - 145. [Abstract] [Full Text] [PDF]
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B. S. Cain, D. R. Meldrum, K. S. Joo, J.-F. Wang, X. Meng, J. C. Cleveland Jr., A. Banerjee, and A. H. Harken Human SERCA2a levels correlate inversely with age in senescent human myocardium J. Am. Coll. Cardiol., August 1, 1998; 32(2): 458 - 467. [Abstract] [Full Text] [PDF]
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J. R. Kersten, T. J. Schmeling, K. G. Orth, P. S. Pagel, and D. C. Warltier Acute hyperglycemia abolishes ischemic preconditioning in vivo Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H721 - H725. [Abstract] [Full Text] [PDF]
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A. Dana, J.-i. Imagawa, D. M Yellon, F. Tomai, F. Crea, A. Gaspardone, and P. A. Gioffre Phentolamine and Preconditioning During Coronary Angioplasty • Response Circulation, July 28, 1998; 98(4): 378 - 379. [Full Text]
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M. Miyamae, M. M. Rodriguez, S. A. Camacho, I. Diamond, D. Mochly-Rosen, and V. M. Figueredo Activation of varepsilon protein kinase C correlates with a cardioprotective effect of regular ethanol consumption PNAS, July 7, 1998; 95(14): 8262 - 8267. [Abstract] [Full Text] [PDF]
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R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]
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T. C. Wascher, J. C. Cleveland, D. R. Meldrum, B. S. Cain, A. Banerjee, and A. H. Harken Sulfonylureas and Cardiovascular Mortality in Diabetes: A Class Effect? • Response Circulation, April 14, 1998; 97(14): 1427 - 1428. [Full Text]
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L. Hebbar, W. V. Houck, J. L. Zellner, B. H. Dorman, and F. G. Spinale Temporal Relation of ATP-Sensitive Potassium-Channel Activation and Contractility Before Cardioplegia Ann. Thorac. Surg., April 1, 1998; 65(4): 1077 - 1082. [Abstract] [Full Text] [PDF]
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D. M Yellon, G. F Baxter, D. Garcia-Dorado, G. Heusch, and M. S Sumeray Ischaemic preconditioning: present position and future directions Cardiovasc Res, January 1, 1998; 37(1): 21 - 33. [Abstract] [Full Text] [PDF]
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F. Tomai, F. Crea, A. Gaspardone, F. Versaci, A. S. Ghini, R. De Paulis, L. Chiariello, and P. A. Gioffre Phentolamine Prevents Adaptation to Ischemia During Coronary Angioplasty : Role of {alpha}-Adrenergic Receptors in Ischemic Preconditioning Circulation, October 7, 1997; 96(7): 2171 - 2177. [Abstract] [Full Text]
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B. H. Dorman, L. Hebbar, R. B. Hinton, R. C. Roy, and F. G. Spinale Preservation of Myocyte Contractile Function After Hypothermic Cardioplegic Arrest by Activation of ATP-Sensitive Potassium Channels Circulation, October 7, 1997; 96(7): 2376 - 2384. [Abstract] [Full Text]
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S.-J. O, M. H. Cox, F. A. Crawford Jr., and F. G. Spinale PROTEIN KINASE C ACTIVATION BEFORE CARDIOPLEGIC ARREST: BENEFICIAL EFFECTS ON MYOCYTE CONTRACTILITY J. Thorac. Cardiovasc. Surg., October 1, 1997; 114(4): 651 - 659. [Abstract] [Full Text]
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Y. Liu, W. D. Gao, B. O'Rourke, and E. Marban Priming effect of adenosine on KATP currents in intact ventricular myocytes: implications for preconditioning Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1637 - H1643. [Abstract] [Full Text] [PDF]
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C. S Carr, R. J Hill, H. Masamune, S. P Kennedy, D. R Knight, W.R. Tracey, and D. M Yellon Evidence for a role for both the adenosine A1 and A3 receptors in protection of isolated human atrial muscle against simulated ischaemia Cardiovasc Res, October 1, 1997; 36(1): 52 - 59. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, Y. Qiu, X.-L. Tang, S. Manchikalapudi, X. Cao, and R. Bolli Ischemic Preconditioning Induces Selective Translocation of Protein Kinase C Isoforms {epsilon} and {eta} in the Heart of Conscious Rabbits Without Subcellular Redistribution of Total Protein Kinase C Activity Circ. Res., September 19, 1997; 81(3): 404 - 414. [Abstract] [Full Text]
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E. Giannella, H.-C. Mochmann, and R. Levi Ischemic Preconditioning Prevents the Impairment of Hypoxic Coronary Vasodilatation Caused by Ischemia/Reperfusion : Role of Adenosine A1/A3 and Bradykinin B2 Receptor Activation Circ. Res., September 19, 1997; 81(3): 415 - 422. [Abstract] [Full Text]
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J. C. Cleveland Jr, D. R. Meldrum, B. S. Cain, A. Banerjee, and A. H. Harken Oral Sulfonylurea Hypoglycemic Agents Prevent Ischemic Preconditioning in Human Myocardium : Two Paradoxes Revisited Circulation, July 1, 1997; 96(1): 29 - 32. [Abstract] [Full Text]
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H. Miyawaki and M. Ashraf Ca2+ as a Mediator of Ischemic Preconditioning Circ. Res., June 19, 1997; 80(6): 790 - 799. [Abstract] [Full Text]
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I. Tritto, D. D'Andrea, N. Eramo, A. Scognamiglio, C. De Simone, A. Violante, A. Esposito, M. Chiariello, and G. Ambrosio Oxygen Radicals Can Induce Preconditioning in Rabbit Hearts Circ. Res., May 19, 1997; 80(5): 743 - 748. [Abstract] [Full Text]
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L. P. Perrault, P. Menasche, A. Bel, T. de Chaumaray, J. Peynet, A. Mondry, P. Olivero, R. Emanoil-Ravier, and J.-M. Moalic ISCHEMIC PRECONDITIONING IN CARDIAC SURGERY: A WORD OF CAUTION J. Thorac. Cardiovasc. Surg., November 1, 1996; 112(5): 1378 - 1386. [Abstract] [Full Text]
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R. L. Engler and D. M. Yellon Sulfonylurea KATP Blockade in Type II Diabetes and Preconditioning in Cardiovascular Disease: Time for Reconsideration Circulation, November 1, 1996; 94(9): 2297 - 2301. [Full Text]
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M. V. Cohen, Y. Liu, G. S. Liu, P. Wang, C. Weinbrenner, G. A. Cordis, D. K. Das, and J. M. Downey Phospholipase D Plays a Role in Ischemic Preconditioning in Rabbit Heart Circulation, October 1, 1996; 94(7): 1713 - 1718. [Abstract] [Full Text]
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P. E. Light, A. A. Sabir, B. G. Allen, M. P. Walsh, and R. J. French Protein Kinase C–Induced Changes in the Stoichiometry of ATP Binding Activate Cardiac ATP-Sensitive K+ Channels: A Possible Mechanistic Link to Ischemic Preconditioning Circ. Res., September 1, 1996; 79(3): 399 - 406. [Abstract] [Full Text]
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C. Vahlhaus, R. Schulz, H. Post, R. Onallah, and G. Heusch No Prevention of Ischemic Preconditioning by the Protein Kinase C Inhibitor Staurosporine in Swine Circ. Res., September 1, 1996; 79(3): 407 - 414. [Abstract] [Full Text]
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G. Brooks and D. J. Hearse Role of Protein Kinase C in Ischemic Preconditioning: Player or Spectator? Circ. Res., September 1, 1996; 79(3): 628 - 631. [Full Text]
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P. Menasche, C. Mouas, and C. Grousset Is Potassium Channel Opening an Effective Form of Preconditioning Before Cardioplegia? Ann. Thorac. Surg., June 1, 1996; 61(6): 1764 - 1768. [Abstract] [Full Text]
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