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PubMed2005

Erythropoietin mimics ischemic preconditioning.

Ischemic preconditioning is a powerful endogenous phenomenon in which brief periods of a sub-toxic ischemic insult induce robust protection against future, lengthy, lethal ischemia. The cardioprotective effects of ischemic preconditioning are manifest in all species studied so far, including humans. The ability to reproduce the cardioprotective effects of ischemic preconditioning with pharmacological agents raises the possibility that a drug may ultimately be introduced into clinical practice to treat human hearts undergoing ischemia/reperfusion. This chapter focuses on erythropoietin (Epo), a drug that has already been approved for humans and is in current use for the treatment of anemia associated with chronic renal failure, HIV infection, cancer patients on chemotherapy, and to reduce allogenic blood transfusion in surgery patients. Several recent studies have suggested that this cytokine possesses properties far beyond its capacity to produce red blood cells such as the ability to protect tissues including brain, kidney and heart against injury caused by ischemia/reperfusion. Cardioprotection conferred by Epo has been shown to be equal in magnitude to that conferred by ischemic preconditioning. However, the underlying mechanisms by which Epo protects the heart against injury caused by ischemia remain unknown.

Animals↗
PubMed2000

Cardiac interstitial bradykinin release during ischemia is enhanced by ischemic preconditioning.

Ischemic preconditioning is known to protect the myocardium from ischemia-reperfusion injury. We examined the transmural release of bradykinin during myocardial ischemia and the influence of ischemic preconditioning on bradykinin release during subsequent myocardial ischemia. Myocardial ischemia was induced by occlusion of the left anterior descending coronary artery in anesthetized cats. Cardiac microdialysis was performed by implantation and perfusion of dialysis probes in the epicardium and endocardium. In eight animals, bradykinin release was greater in the endocardium than in the epicardium (14.4 +/- 2.8 vs. 7.3 +/- 1.7 ng/ml, P < 0.05) during 30 min of ischemia. In seven animals subjected to preconditioning, myocardial bradykinin release was potentiated significantly from 2.4 +/- 0.6 ng/ml during the control period to 23.1 +/- 2.5 ng/ml during 30 min of myocardial ischemia compared with the non-preconditioning group (from 2.7 +/- 0.6 to 13.4 +/- 1.9 ng/ml, P < 0.05, n = 6). Thus this study provides further evidence that transmural gradients of bradykinin are produced during ischemia. The results also suggest that ischemic preconditioning enhances bradykinin release in the myocardial interstitial fluid during subsequent ischemia, which is likely one of the mechanisms of cardioprotection of ischemic preconditioning.

Animals↗
PubMed2002

PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning.

Ischemic preconditioning results in an immediate phase of protection against lethal ischemia/reperfusion injury that is comprised of both irreversible necrosis and programmed cell death, apoptosis. We hypothesized that preconditioning may activate putative anti-apoptotic pathways, through the induction of either phosphatidyl inositol 3-OH kinase (PI3 kinase) or p42/p44 extracellular receptor kinase, attenuating total cell death. Isolated perfused rat hearts were preconditioned with two cycles of 5 min ischemia and 10 min reperfusion. Then they were frozen for Western blot analysis or subjected to 35 min regional ischemia and 120 min reperfusion prior to infarct size assessment. Selective PI3 kinase inhibitors, wortmannin (W, 100 n M) and LY294002 (LY, 15 microM) and the p42/p44 inhibitor, PD 98059 (PD, 10 and 50 microM), were individually infused during the preconditioning protocol. One further group of hearts received both inhibitors (W and PD). The results were expressed as percentage of infarction within the risk zone. Inhibition of PI3 kinase by either W or LY partially abrogated the infarct sparing effect of ischemic preconditioning (I/R%: 44.6+/-2.7 in C, 17.6+/-2.0 in IP, vs 32.2+/-4.2 in W, and 30.9+/-2.6 in LY, P<0.05). Inhibition of ERK phosphorylation however, had no significant effect upon infarct size reduction (17.6+/-2.0 in ischemic preconditioning vs 21.4+/-3.0 in IP+10 microM PD and 15.2+/-1.4 in IP+50 microM PD, P>0.05). Western blot analysis confirmed that PD abrogated the phosphorylation of p42/p44 and LY the phosphorylation of AKT. Combined inhibition with PD+W failed to further attenuate protection (27.6+/-1.3%, P>0.1). These data appear to demonstrate that the PI3 kinase, but not the p42/p44 cascade, is implicated in early ischemic preconditioning.

Androstadienes↗
PubMed1996

Myocardial, neural and vascular aspects of ischemic preconditioning.

Ischemic preconditioning can be obtained with brief coronary occlusions. It has been studied in different animal species including dogs, pigs, rabbits and rats. The suggested duration of the occlusions ranges from four periods of 5 min, separated from each other by 5 min of reperfusion, to one period of 2.5 min. In addition to the reduction of the size of a subsequent infarction, preconditioning is responsible for the attenuation of the ischemia-reperfusion injury. The protection has a short duration and does not exceed two hours. Myocardial, neural and endothelial factors are involved in preconditioning. The myocardial component includes an increased release of adenosine with activation of A1 adenosine receptors, the activation of a protein-kinase C and possibly of antioxidant enzymes. The neural component includes a reduction in the release of noradrenaline from the postganglionic sympathetic fibers and a reduced myocardial sensitivity to noradrenaline. The increased myocardial release of adenosine, together with the reduced adrenergic activity, is consistent with the reduction in myocardial metabolism which has been observed after preconditioning. The coronary vascular endothelium is concerned in an increased release of nitric oxide which seems to be responsible for a prevention of reperfusion arrhythmias. In addition to the protective effect exerted on the myocardium, ischemic preconditioning seems to be responsible for a change in the coronary responsiveness to short periods of occlusion followed by release. This change in responsiveness is mainly represented by a greater velocity of the increase in flow occurring in the coronary reactive hyperemia.

Animals↗
PubMed1996

Synergistic modulation of ATP-sensitive K+ currents by protein kinase C and adenosine. Implications for ischemic preconditioning.

Ischemic preconditioning has been shown to involve the activation of adenosine receptors, protein kinase C (PKC), and ATP-sensitive K+ (K ATP) channels. We investigated the effects of PKC activation and adenosine on K(ATP) current (I KATP) and action potentials in isolated rabbit ventricular myocytes. Responses to pinacidil (100 to 400 micromol/L), an opener of K(ATP) channels, were markedly increased by preexposure to the PKC activator phorbol 12-myristate 13-acetate (PMA, 100 nmol/L). I(KATP) measured at 0 mV was increased by PMA pretreatment from 0.55 +/- 0.32 to 3.25 +/- 0.47 nA (n=6, P < .01). We next determined whether PKC activation abbreviates the time required to turn on I(KATP) developed after an average of 15.1 +/- 2.4 minutes (n=8). Ten-minute pretreatment with PMA alone (PMA+MI) did not significantly alter this latency (11.9 +/- 2.0 minutes, n=8). Since adenosine receptor activation has been shown to play an important role in the preconditioning response, two groups of myocytes were studied with adenosine (10 micromol/L) included during MI. Without PMA, adenosine alone (MI+Ado) did not affect the latency to develop I(KATP) (12.3 +/- 1.5 minutes, n=8). However, if cells were pretreated with PMA and then subjected to MI in the presence of adenosine (PMA+MI+Ado), the latency was greatly shortened to 5.5 +/- 1.6 minutes (n=8;P < .02 versus MI, PMA+MI, and MI+Ado groups). This effect could not be reproduced by an inactive phorbol but was completely abolished by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline. The opening of K(ATP) channels may be cardioprotective because of the abbreviation of action potential duration (APD) during ischemia. Therefore, we tested whether PKC activation could modify the time course of APD shortening during MI. Consistent with the ionic current measurements, PMA pretreatment significantly accelerated APD shortening, but only when adenosine (10 micromol/L) was included during MI. The effects were not attributable to accelerated ATP consumption: PMA pretreatment did not alter the time required to induce rigor during MI, whether or not adenosine was included. Our results indicate that PKC activation increases the I(KATP) Induced by pinacidil or by MI. The latter effect requires concomitant adenosine receptor activation. The synergistic modulation of I(KATP) by PKC and adenosine provides an explicit basis for current paradigms of ischemic preconditioning.

Adenosine↗
PubMed2003

Cardio-protective determinants are conserved in aged human myocardium after ischemic preconditioning.

Ischemic preconditioning (IPrec) improves post-ischemic dysfunctions of the myocardium along with activation of protein kinase C isozymes including PKCdelta. Moreover, expression of cardio-protective determinants can reduce ischemic damages. Because IPrec is limited in aged hearts, we assessed in an experimental model the impact of aging on PKCdelta and selected protective proteins in the preconditioned myocardium from adult (< or =55) and older (> or =70 years) humans. Adult myocardium showed PKCdelta up-regulation after IPrec along with improved post-ischemic contractility. Although there was no functional benefit, PKCdelta increased in older myocardium as well. Subsequent mRNA analyses demonstrated that IPrec stabilizes the mRNA expression of protective proteins (Hsp70, Bcl-2/-xL, IAPs) in both aging groups. Moreover, older hearts revealed increase in post-ischemic Hsp90beta. Our study indicates, that IPrec conserves the expression of cardio-protective determinants in aged hearts despite limited functional recovery.

Actins↗
PubMedDate not supplied

Sarcolemmal and mitochondrial K(ATP) channels and myocardial ischemic preconditioning.

Ischemic preconditioning (IPC) is the phenomenon whereby brief periods of ischemia have been shown to protect the myocardium against a sustained ischemic insult. The result of IPC may be manifest as a marked reduction in infarct size, myocardial stunning, or incidence of arrhythmias. While many substances and pathways have been proposed to play a role in the signal transduction mediating the cardioprotective effect of IPC, overwhelming evidence indicates an intimate involvement of the ATP-sensitive potassium channel (K(ATP) channel) in this process. Initial hypotheses suggested that the surface or sarcolemmal K(ATP) (sarcK(ATP)) channel mediated the cardioprotective effects of IPC. However, much research has subsequently supported a major role for the mitochondrial K(ATP) channel (mitoK(ATP)) as the one involved in IPC-mediated cardioprotection. This review presents evidence to support a role for the sarcK(ATP) or the mitoK(ATP) channel as either triggers and/or downstream mediators in the phenomenon of IPC.

Adenosine Triphosphate↗
PubMed2002

Kidney ischemic preconditioning.

Ischemic injury to the kidney is associated with high morbidity and mortality. Improving the ability of the kidney to tolerate ischemic injury would have important implications. A significant amount of data now exists to suggest that there may be intrinsic mechanisms brought to bear by the kidney when exposed to a toxic or ischemic insult, which protect it against a subsequent exposure to ischemia. While it is frequently stated that this phenomenon, termed ischemic preconditioning, was first described in the heart, in fact there is almost a century of literature on the kidney that supports the concept that prior injury protects against a second insult. The protective effect of preconditioning is greater than most reported protective effects with pharmacological interventions in animals. There is compelling evidence in other organs that preconditioning occurs in humans. It therefore behooves us to understand the endogenous processes that the kidney has developed to protect itself against an ischemic insult. Armed with this understanding we can then attempt to mimic these processes and thereby prevent and treat ischemic acute renal failure.

Animals↗
PubMed2003

Induction of cellular resistance against Kupffer cell-derived oxidant stress: a novel concept of hepatoprotection by ischemic preconditioning.

Ischemic preconditioning (IP) triggers protection of the liver from prolonged subsequent ischemia. However, the underlying protective mechanisms are largely unknown. We investigated whether and how IP protects the liver against reperfusion injury caused by Kupffer cell (KC)-derived oxidants. IP before 90 minutes of warm ischemia of rat livers in vivo significantly reduced serum alanine aminotransferase (AST) levels and leukocyte adherence to sinusoids and postsinusoidal venules during reperfusion. This protective effect was mimicked by postischemic intravenous infusion of glutathione (GSH), an antioxidative strategy against KC-derived H(2)O(2). Interestingly, no additional protection was achieved by infusion of GSH to preconditioned animals. These findings and several additional experiments strongly suggest IP mediated antioxidative effects: IP prevented oxidant cell injury in isolated perfused rat livers after selective KC activation by zymosan. Moreover, IP prevented cell injury and pertubations of the intracellular GSH/GSSG redox system caused by direct infusion of H(2)O(2) (0.5 mmol/L). IP-mediated resistance against H(2)O(2) could neither be blocked by the adenosine A2a antagonist DMPX nor mimicked by A2a agonist CGS21680. In contrast, H(2)O(2) resistance was abolished by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, but induced when p38 MAPK was directly activated by anisomycin. In conclusion, we propose a novel concept of hepatoprotection by IP: protection of liver cells by enhancing their resistance against KC-derived H(2)O(2). Activation of p38 MAPK and preservation of the intracellular GSH/oxidized glutathione (GSSG) redox system, but not adenosine A2a receptor stimulation, seems to be pivotal for the development of H(2)O(2) resistance in preconditioned livers.

Animals↗
PubMed1997

Mechanisms of ischemic preconditioning.

Ischemic preconditioning (IPC) refers to a phenomenon in which a tissue is rendered resistant to the deleterious effects of prolonged ischemia by previous exposure to brief periods of vascular occlusion. While the beneficial effects of IPC were first demonstrated in the myocardium, it is now clear that preconditioning protects postischemic skeletal muscle, brain, and small intestine and may also occur in humans. Although first described over a decade ago, the mechanisms underlying the powerful protective effects of IPC remain uncertain. However, a growing body of evidence indicates that the beneficial actions of IPC involve the activation of adenosine A1 receptors during the period of preconditioning ischemia in most organs and species. Adenosine A1 receptor stimulation is thought to promote the translocation and activation of specific isoforms of protein kinase C1 which in turn phosphorylate as yet unidentified cellular effector molecules. In the heart, it has been suggested that ATP-sensitive potassium channels may represent important effectors of the preconditioning phenomenon. In contrast, ATP-sensitive potassium channel activation does not seem to contribute to the beneficial effects of IPC in the small bowel and seems to play only a limited role in skeletal muscle. In these peripheral tissues, the beneficial effects of IPC are related to inhibition of leukocyte adhesion and emigration. In the small intestine, IPC seems to prevent postischemic leukocyte adhesion by maintaining the bioavailability of nitric oxide (a potent endogenous anti-adhesive agent) and preventing, the expression of P-selectin (an adhesive molecule expressed by endothelial cells that is thought to modulate leukocyte rolling). In skeletal muscle, these actions are mediated by an effect of IPC to augment the production of adenosine (another potent endogenous anti-adhesive agent) during reperfusion. Thus, although adenosine-induced protein kinase C activation seems to play an important role in initiating the beneficial actions of IPC in most tissues, the effector of the preconditioning phenomenon seems to differ among tissues. Understanding the mechanisms of IPC has led to the recognition that tissues may also be preconditioned by administration of agents that act via the same signaling cascade (e.g., adenosine, bradykinin, alpha 1-adrenergic agonists). The purpose of this review is to summarize the evidence regarding the mechanisms of IPC in different organs.

Animals↗
PubMed2006

Decreased capacity of immune cells to cause tissue injury mediates kidney ischemic preconditioning.

Ischemic preconditioning (IP) is a well-established phenomenon, and the underlying mechanisms of IP are thought to involve adaptive changes within the injured tissue. Because one of the main functions of immune cells is to harbor memory, we hypothesized that circulating immune cells could mediate IP by responding to an initial ischemia reperfusion injury (IRI) and then mediate decreased injury after a second IRI event. C57BL/6 mice underwent 30 min of bilateral renal clamping or sham operation. At 5 days after ischemia, purified leukocytes from spleen were adoptively transferred into T cell-deficient (nu/nu) mice. After 1 wk, these mice underwent 30 min of renal IRI. The nu/nu mice receiving leukocytes from ischemic wild-type mice had significantly reduced renal injury compared with nu/nu mice receiving leukocytes from sham-operated, wild-type mice. Infiltration of neutrophil and macrophage in postischemic kidney did not correlate with the protection. No difference in kidney C3d or IgG deposition was detected between groups. Given that inducible NO synthase (iNOS) has been implicated in IP, leukocytes from ischemic or sham-operated, iNOS-deficient mice were transferred into nu/nu mice. Effects similar to those of wild-type transfer of ischemic leukocytes were demonstrated; thus, iNOS was not mediating the IP effect of leukocytes. This is the first evidence that immune cells are primed after renal IRI and thereby lose the capacity to cause kidney injury during a second episode of IRI. This finding may also be relevant for elucidating the mechanisms underlying cross-talk between injured kidney and distant organs.

Adoptive Transfer↗
PubMed2004

Reactive oxygen species as mediators of signal transduction in ischemic preconditioning.

Ischemic preconditioning (IPC) is a most powerful endogenous mechanism for myocardial protection against ischemia/reperfusion injury. It is now apparent that reactive oxygen species (ROS) generated in the mitochondrial respiratory chain act as a trigger of IPC. ROS mediate signal transduction in the early phase of IPC through the posttranslational modification of redox-sensitive proteins. ROS-mediated activation of Src tyrosine kinases serves a scaffold for interaction of proteins recruited by G protein-coupled receptors and growth factor receptors that is necessary for amplification of cardioprotective signal transduction. Protein kinase C (PKC) plays a central role in this signaling cascade. A crucial target of PKC is the mitochondrial ATP-sensitive potassium channel, which acts as a trigger and a mediator of IPC. Mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun NH(2)-terminal kinase) are thought to exist downstream of the Src-PKC signaling module, although the role of MAP kinases in IPC remains undetermined. The late phase of IPC is mediated by cardioprotective gene expression. This mechanism involves redox-sensitive activation of transcription factors through PKC and tyrosine kinase signal transduction pathways that are in common with the early phase of IPC. The effector proteins then act against myocardial necrosis and stunning presumably through alleviation of oxidative stress and Ca(2+) overload. Elucidation of IPC-mediated complex signaling processes will help in the development of more effective pharmacological approaches for prevention of myocardial ischemia/reperfusion injury.

Animals↗
PubMed1996

Cardioprotection by ischemic and nonischemic myocardial stress and ischemia in remote organs. Implications for the concept of ischemic preconditioning.

Ischemic preconditioning studies employ one or more brief total coronary artery occlusions separated by complete reperfusion to limit infarct size during a subsequent prolonged coronary artery occlusion. We now present evidence that in anesthetized pigs a partial coronary artery occlusion without intervening reperfusion between the partial and prolonged total occlusions can also precondition the myocardium provided that the reduction in coronary blood flow is sufficiently severe. Thus infarct size was reduced after a 60 min total coronary artery occlusion when the total occlusion was preceded by a partial coronary occlusion that reduced coronary blood flow by 70% but not when the flow reduction was only 30%. In this two-stage coronary occlusion model the degree of protection appears greater in the epicardial than in the endocardial half. In view of evidence that brief occlusions of a coronary artery also protect myocardium outside its perfusion territory, we subsequently investigated whether ischemia in remote organs can protect myocardium. Because of reports that development of infarct size may be temperature dependent, we also investigated whether the cardioprotection by remote organ ischemia was temperature dependent. In anesthetized rats a 15 min coronary artery occlusion was more effective in reducing infarct size produced by a subsequent 60 min total coronary artery occlusion when the experiments were performed at a body core temperature of 30-31 degrees C than at 36-37 degrees C, while infarct size of animals which were subjected to only the 60 min total coronary artery occlusion was the same for the two body core temperatures. In rats with a body core temperature of 36-37 degrees C a 15 min mesenteric artery occlusion, but not a 15 min renal artery occlusion, reduced infarct size produced by a subsequent 60 min coronary artery occlusion. When the experiments were performed at 30-31 degrees C both the mesenteric and renal artery occlusions were protective. These observations indicate the local myocardial ischemia is not required to protect the myocardium during a prolonged coronary occlusion. We further investigated whether myocardium could also be protected by a cardiac stimulus which does not produce ischemia at all. For this purpose we electrically paced the left ventricle of anesthetized pigs to produce heart rates of 200 bpm (which did not lead to ischemia as assessed by a number of functional and biochemical variables) and found that 30 min of ventricular pacing reduced myocardial infarct size produced by a subsequent 60 min coronary artery occlusion. The protection by ventricular pacing involved activation of K+ATP channels as pretreatment with glibenclamide abolished the protection by ventricular pacing. We conclude that a number of distinctly different stimuli can protect the myocardium suggesting that ischemic myocardial preconditioning could be just one feature of a more general protection phenomenon.

Animals↗
PubMed2003

Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning.

Ischemic preconditioning (Pre-con) is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. We tested the hypothesis that repetitive ischemia applied during early reperfusion, i.e., postconditioning (Post-con), is cardio-protective by attenuating reperfusion injury. In anesthetized open-chest dogs, the left anterior descending artery (LAD) was occluded for 60 min and reperfused for 3 h. In controls (n = 10), there was no intervention. In Pre-con (n = 9), the LAD was occluded for 5 min and reperfused for 10 min before the prolonged occlusion. In Post-con (n = 10), at the start of reperfusion, three cycles of 30-s reperfusion and 30-s LAD reocclusion preceded the 3 h of reperfusion. Infarct size was significantly less in the Pre-con (15 +/- 2%, P < 0.05) and Post-con (14 +/- 2%, P < 0.05) groups compared with controls (25 +/- 3%). Tissue edema (% water content) in the area at risk was comparably reduced in Pre-con (78.3 +/- 1.2, P < 0.05) and Post-con (79.7 +/- 0.6, P < 0.05) versus controls (81.5 +/- 0.4). Polymorphonuclear neutrophil (PMN) accumulation (myeloperoxidase activity, Deltaabsorbance.min-1.g tissue-1) in the area at risk myocardium was comparably reduced in Post-con (10.8 +/- 5.5, P < 0.05) and Pre-con (13.4 +/- 3.4, P < 0.05) versus controls (47.4 +/- 15.3). Basal endothelial function measured by PMN adherence to postischemic LAD endothelium (PMNs/mm2) was comparably attenuated by Post-con and Pre-con (15 +/- 0.6 and 12 +/- 0.6, P < 0.05) versus controls (37 +/- 1.5), consistent with reduced expression of P-selectin on coronary vascular endothelium in Post-con and Pre-con. Endothelial function assessed by the maximal vasodilator response of postischemic LAD to acetylcholine was significantly greater in Post-con (104 +/- 6%, P < 0.05) and Pre-con (109 +/- 5%, P < 0.05) versus controls (71 +/- 8%). Plasma malondialdehyde (microM/ml), a product of lipid peroxidation, was significantly less at 1 h of reperfusion in Post-con (2.2 +/- 0.2, P < 0.05) versus controls (3.2 +/- 0.3) associated with a decrease in superoxide levels revealed by dihydroethidium staining in the myocardial area at risk. These data suggest that Post-con is as effective as Pre-con in reducing infarct size and preserving endothelial function. Post-con may be clinically applicable in coronary interventions, coronary artery bypass surgery, organ transplantation, and peripheral revascularization where reperfusion injury is expressed.

Animals↗
PubMed1997

Signal transduction in ischemic preconditioning.

Ischemic preconditioning is a phenomenon in which exposure of the heart to a brief period of ischemia causes it to quickly adapt itself to become resistant to infarction from a subsequent ischemic insult. The mechanism is not fully understood but, at least in the rabbit, it is known to be triggered by occupation of adenosine receptors, opioid receptors, bradykinin receptors and the generation of free radicals during the preconditioning ischemia. All of these are thought to converge on and activate protein kinase C (PKC), which in turn activates a tyrosine kinase. This kinase cascade eventually terminates on some unknown effector, possibly a potassium channel or a cytoskeletal protein, which makes the cells resistant to infarction. If this process can be understood, it should be possible to devise a method for conferring this protection to patients with acute myocardial infarction.

Adaptation, Physiological↗
PubMed2002

Protection from AMP 579 can be added to that from either cariporide or ischemic preconditioning in ischemic rabbit heart.

AMP 579, an adenosine A /A receptor agonist, is cardioprotective when administered at reperfusion. Pretreatment with the Na /H exchanger inhibitor cariporide or ischemic preconditioning (PC) also limits infarct size. To gain insight into the mechanism of AMP 579 we investigated whether its protection could be added to that from either cariporide or PC. rabbit hearts were subjected to 45 min of regional ischemia followed by 3 h of reperfusion. Infarct size in the control group was 55.8 +/- 3.9% of the risk zone. PC significantly reduced infarct size to 26.0 +/- 6.7% (p<0.05). AMP 579 (30 micro g/kg) given just before reperfusion followed by 3 micro g/kg/min infusion for 70 min also limited infarct size (32.1 +/- 1.8%,) but the combination of AMP 579 and PC showed a significantly greater limitation of infarct size (5.5 +/- 2.7%, p < 0.05). Because cariporide pretreatment was so protective (8.5 +/- 3.7% infarction), we had to increase the ischemic insult to 60 min to test for any additive effect of the combination of AMP 579 + cariporide. Infarct size in the untreated group was 66.0 +/- 4.9% of the risk zone. Cariporide (0.5 mg/kg) 5 min prior to ischemia significantly reduced infarct size to 41.5 +/- 7.7%. When cariporide pre-treatment was combined with AMP 579 at reperfusion, infarction was further limited (14.2 +/- 4.5%). Because AMP 579's protection can be added to that of either cariporide or PC, AMP 579's mechanism of protection probably differs from either of them. The combination of AMP 579 + cariporide was particularly efficacious and could be useful in the surgical setting.

Animals↗
PubMed1998

Biochemical and ultrastructural evaluations of the effect of ischemic preconditioning on ischemic myocardial injury--role of the adenosine triphosphate-sensitive potassium channel.

The aim of this study was to clarify the role of the adenosine triphosphate (ATP)-sensitive potassium channel on the mechanism of ischemic preconditioning (IP). Thirty-five anesthetized dogs were divided into 5 groups: (1) Control (C), (2) IP, (3) intravenous infusion of nicorandil (Ni) prior to IP, (4) glibenclamide (G1) pretreated with IP (G1+IP), and (5) G1 pretreated with Ni (G1+Ni). All groups had 60 min ischemia followed by 60 min reperfusion, and were analyzed by biochemical and morphological procedures. At the end of the 60-min reperfusion, %segment shortening in C indicated paradoxical bulging. This value had significantly recovered in IP and Ni groups, but it was still negative in the G1+IP and G1+Ni groups. Ca++-ATPase activity of the sarcoplasmic reticulum (SR) was significantly decreased in C. In the IP and Ni groups, this activity was significantly maintained; however, in the G1+IP and G1+Ni groups it was similar to that in C. State 3 respiration of mitochondria showed similar changes in the SR. In the ultrastructural observations, severely damaged cells were not observed in the IP and Ni groups. These results indicated that an ATP-sensitive potassium channel opener enhanced the effects of IP and its blockade abolished these phenomena. It was conclude that the ATP-sensitive potassium channel may play a key role in the mechanism of IP.

Adenosine Triphosphate↗
PubMed1996

Paradoxical effect of ischemic preconditioning on ischemic contracture? NMR studies of energy metabolism and intracellular pH in the rat heart.

Using the blood-perfused rat heart, we have previously shown that although ischemic preconditioning (PC) and cardioplegia (CP) afforded similar protection against post-ischemic contractile dysfunction this effect was not additive even though PC accelerated whereas CP delayed ischemic contracture. Using NMR we examined the effects of these interventions on pHi and ATP metabolism during global ischemia. Isolated rat hearts (n = 6/group) with an intraventricular balloon were aerobically perfused with buffer, subjected to zero flow ischemia (37 degrees C) for 35 min and reperfused for 40 min. The groups were: (1) controls without protection, (2) PC (2 cycles), and (3) St Thomas' cardioplegia, prior to test ischemia. PC accelerated whereas CP delayed ischemic contracture (P < 0.05 v controls). Yet, after 40 min reperfusion, both interventions produced substantial improvements in the recovery of LVDP (P < 0.05 v controls). During 35 min ischemia, the decline of ATP was delayed by CP but accelerated by PC (P < 0.05 v controls). The pHi fell steeply in controls to a plateau of 5.9 after 14 min ischemia. PC had no effect on the rate of fall of pHi but reduced its extent (P < 0.05). CP delayed the onset of the decline in pHi (P < 0.05) but, once initiated, there was no effect on the rate of decline to a plateau. Thus, despite protecting post-ischemic contractile function, PC accelerated ischemic contracture and the depletion of ATP, but substantially reduced intracellular acidosis. In contrast, CP slowed ischemic contracture and the depletion of ATP; it also delayed the onset of acidosis.

Animals↗