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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phenomenon of ischaemic preconditioning, highlights a new and endogenous route to myocardial protection, which we believe could be exploited in our search for new therapeutic ways to protect the infarcting myocardium. Ischaemic preconditioning has been shown to be associated with both an early, or acute phase of protection lasting approximately 1-2 hours, as well as a delayed phase or "second window of protection" seen at least 24 hours following the initial sublethal ischaemic insult, and lasting up to 72 hours. We believe that both responses are triggered by similar receptor mediated events in addition to using the similar signalling pathways involving kinase cascades. However it is thought that the ultimate target or end-effector through which the protection is manifest may be different for the early vs. late effects. Some evidence exists that the end-effector involved in early preconditioning may be via the ATP-sensitive potassium channel (K(ATP)). With respect to the second window of protection, the cellular mechanisms underlying this are not fully understood at present, however we believe that they may be dependent upon a similar signalling transduction pathway with upregulation of cytoprotective proteins such as the heat stress proteins, and/or anti-oxidant proteins. Evidence demonstrating that preconditioning can occur in the human myocardium is also accumulating. In this respect cultured human ventricular myocytes as well as human atrial muscle have been shown to be preconditioned with brief episodes of simulated ischemia. These human preparations also respond to the known triggers and possible end-effectors of preconditioning, (e.g. adenosine receptor stimulation and K(ATP) channel opening) as well as being able to elicit their responses through the PKC signalling pathway. Further support for this phenomenon, in man, comes from PTCA studies demonstrating that this invasive procedure can put patients into a "preconditioned state"; this effect being associated with reduced ischaemic symptoms as well as the involvement of the adenosine receptor and K(ATP) channel. Of further interest is the observation that patients with a previous history of angina, prior to a MI, sustain smaller infarcts and have an improved survival. However the most direct evidence that preconditioning occurs in man comes from studies in patients undergoing coronary artery bypass surgery. The above evidence that preconditioning can occur in man makes it now possible to begin to design clinical studies investigating cardioprotective properties of drugs that can specifically mimic this phenomenon.
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PMID:Myocardial adaptation to ischaemia--the preconditioning phenomenon. 1032 17

Release of the excitotoxic amino acid, glutamate, into the extracellular space during ischemia/reperfusion contributes to neuronal injury and death. To gain insights into the signal transduction pathways involved in glutamate release we examined the time course of changes in enzyme levels and activities of cPLA2, PKC and ERKs in the rat cerebral cortex after four vessel (4VO) ischemia followed by reperfusion. Measurement both by enzymatic assay and Western blot analysis showed significant increases in the activity and protein levels of cPLA2 during 10-20 min of ischemia. Activity remained elevated at 10 min and 20 min of reperfusion, whereas cPLA levels had returned to base line levels after 20 min of reperfusion. PKC activity increased significantly in the particulate, but not in the cytosolic, fractions both during ischemia and reperfusion. Increases in PKCgamma levels were recorded in the particulate fraction during ischemia and reperfusion, and in the cytosolic fraction during ischemia. Western blot analysis with a phosphospecific antibody for characterization of MAPK (ERKs) activation revealed significantly increased phosphorylation of ERK1 and ERK2 in the particulate fraction, of ERK2 in the cytosolic fraction, during ischemia and of both enzymes in the particulate and cytosolic fractions after 10 min of reperfusion. The relevance of the results to glutamate release is discussed.
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PMID:Activation of cPLA2, PKC, and ERKs in the rat cerebral cortex during ischemia/reperfusion. 1034 96

Mibefradil is a novel calcium channel blocker with activity at both L-type and T-type calcium channels. There are data suggesting that this compound can protect the ischemic/reperfused myocardium in spite of the fact that there is a very low abundance of T-type calcium channels within ventricular tissue. The aims of this study were two-fold. First, we wished to study the protective effect of mibefradil on ischemia/reperfusion injury in the isolated rat heart using infarct size as the endpoint of injury. In this respect, we compared mibefradil with amlodipine, a well-known and potent L-type calcium channel blocker, and with ischemic preconditioning, an intervention known to reduce infarct size consistently. Secondly, we investigated the possible mechanisms through which protection was achieved. For this second purpose, we examined the effects on protection of glibenclamide (an ATP-dependent K+ channel blocker) and chelerythrine (a protein kinase C inhibitor). Isolated rat hearts were perfused in the Langendorff mode at constant pressure. Control, mibefradil-treated (0.3 microM), mibefradil plus glibenclamide (50 microM), and mibefradil plus chelerythrine (10 microM) treated hearts underwent 35 minutes regional ischemia followed by 120 minutes reperfusion. At the end of the experiments, infarct size was determined with triphenyltetrazolium chloride and was expressed as a percentage of the ischemic risk zone (I/R%). A significant reduction in infarct size with mibefradil treatment was observed (I/R 11.1 +/- 2.1% vs. 35.5 +/- 3.1% in controls). This was comparable with the infarct reduction seen with two 5-minute cycles of ischemic preconditioning (17.7 +/- 2.5%). Amlodipine 0.1 microM, a concentration that caused equivalent coronary vasodilatation as that produced by mibefradil treatment, had no significant effect on infarct size (I/R 29.7 +/- 3.5%). The protective effect of mibefradil was not significantly modified by the presence of the PKC inhibitor chelerythrine 10 microM (I/R 19.1 +/- 4.9%) but was abolished when glibenclamide 50 microM was coadministered with mibefradil prior to ischemia (I/R 28.1 +/- 4.7%). Neither chlelerythrine nor glibenclamide alone had any influence on infarct size. We conclude from these data that mibefradil, unlike amlodipine, markedly reduces infarct size in the rat isolated heart. This protection is sensitive to inhibition by glibenclamide, suggesting that KATP channel opening may be an important additional and novel mechanism of mibefradil's action.
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PMID:Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. 1037 26

The signal transduction pathways by which ischemia-reperfusion leads to apoptosis may involve the JNK pathway, ceramide generation, and inhibition of protective PKC pathways. The biochemical events associated with apoptosis include mitochondrial inactivation, cytochrome c dislocation, caspase activation, and cytoplasmic acidification. Through the concerted efforts of multiple classes of enzymes, apoptosis is accomplished, resulting in the death of a cell in which potentially transforming oncogenes have been degraded and inflammatory contents are contained within the plasma membrane until the fragments can be ingested by phagocytes. This non-inflammatory mode of cell death permits tissue remodeling with minimal scar formation, and so is preferable to necrotic cell death. The distinction between apoptosis and necrosis, which implies different mechanisms of cell death, is blurred in the case of a pathologic insult such as ischemia-reperfusion. It is suggested that it is more useful to view cell death in the context of whether or not it can be prevented.
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PMID:Apoptosis in myocardial ischemia-reperfusion. 1041 51

Because tyrosine kinase blockade prevents protection by ischemic preconditioning (p.c.) in several species, activation of tyrosine kinase appears to be critical for cardioprotection. The tyrosine kinase's identity, however, is unknown. The present study tested whether activation of a receptor tyrosine kinase, the insulin receptor, could mimic p.c. and if the mechanism of protection was similar to that of p.c. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Infarct size in control hearts was 32.6 +/- 2.3%. A 5-min infusion of insulin (5 mU/ml) followed by a 10-min washout period prior to ischemia significantly reduced infarction to 14.7 +/- 2.1% (P < 0.05). The tyrosine kinase inhibitor genistein (50 microM) given around the insulin infusion blocked protection (28.9 +/- 2.8%). However, when present during the onset of ischemia, genistein had no effect on protection triggered by insulin (14.0 +/- 2.4%; P < 0.05). Inhibition of either PKC by polymyxin B (50 microM) or KATP channels by 5-hydroxydecanoate (100 microM) also failed to prevent protection by insulin (17.5 +/- 3.2% and 17.6 +/- 3.0%, respectively). However, the reduction in infarct size by insulin was significantly attenuated by wortmannin (100 nM), a selective inhibitor of phosphatidylinositol 3-kinase (PI3K, 28.3 +/- 2.2%). Insulin was still able to protect the heart when given only during the reperfusion period (13.2 +/- 3.4%). P.c. reduced infarction to 12.8 +/- 2.0% (P < 0.05) and still offered significant protection in the presence of wortmannin (22.1 +/- 2.4%; P < 0.05). In conclusion, activation of the insulin receptor reduces infarct size in the rabbit heart even when instituted upon reperfusion. However, the mechanism of protection is quite different from that of p.c. and involves activation of PI3K but not PKC or KATP channels.
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PMID:Myocardial protection by insulin is dependent on phospatidylinositol 3-kinase but not protein kinase C or KATP channels in the isolated rabbit heart. 1042 37

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
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PMID:Adenosine and cardioprotection in the diseased heart. 1047 69

Protein kinase C (PKC) is involved in the second messenger signaling cascade during ischemic and Ca(2+) preconditioning. Given that the pharmacological activation of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels also mimics preconditioning, the mechanisms linking PKC activation and mitoK(ATP) channels remain to be established. We hypothesize that PKC activity is important for the opening of the mitoK(ATP) channel. To examine this, a specific opener of the mitoK(ATP) channel, diazoxide, was used in conjunction with subcellular distribution of PKC in a model of ischemia/reperfusion (I/R). Langendorff-perfused rat hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Effects of activation of the mitoK(ATP) channel and other interventions on functional, biochemical, and pathological changes in ischemic hearts were assessed. In hearts treated with diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly improved after I/R; lactate dehydrogenase release was also significantly decreased. The morphology was well preserved in diazoxide-treated hearts compared with nontreated ischemic control hearts. The salutary effects of diazoxide on the ischemic injury were similar to those of Ca(2+) preconditioning. Administration of sodium 5-hydroxydecanoate, an effective blocker of the mitoK(ATP) channel, or chelerythrine or calphostin C, an inhibitor of PKC, during diazoxide pretreatment or during continuous presence of diazoxide in the ischemic period, completely abolished the beneficial effects of the diazoxide on the I/R injury. Blockade of Ca(2+) entry during diazoxide treatment by inhibiting the L-type Ca(2+) channel with verapamil also completely reversed the beneficial effect of diazoxide during I/R. PKC-alpha was translocated to sarcolemma, whereas PKC-delta was translocated to the mitochondria and intercalated disc, and PKC-epsilon was translocated to the intercalated disc of the diazoxide-pretreated hearts. Colocalization studies for mitochondrial distribution with tetramethylrhodamine ethyl ester (TMRE) and PKC isoforms by immunoconfocal microscopy revealed that PKC-delta antibody specifically stained the mitochondria. ATP was significantly increased in the diazoxide-treated hearts. Moreover, the data suggest that activation and translocation of PKC to mitochondria appear to be important for the protection mediated by mitoK(ATP) channel.
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PMID:Activation of mitochondrial ATP-sensitive K(+) channel for cardiac protection against ischemic injury is dependent on protein kinase C activity. 1052 Dec 47

Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). epsilon Protein kinase C (epsilonPKC) has been suggested to mediate preconditioning. Here, we describe an epsilonPKC-selective agonist octapeptide, psiepsilon receptor for activated C-kinase (psiepsilonRACK), derived from an epsilonPKC sequence homologous to its anchoring protein, epsilonRACK. Introduction of psiepsilonRACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased epsilonPKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that epsilonPKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this epsilonPKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.
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PMID:Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation. 1053 2

Ischemic preconditioning (IPC) prevents the deleterious effects of prolonged ischemia and reperfusion (I/R). Because leukocyte infiltration is required to produce the microvascular dysfunction induced by I/R in the small intestine, and P-selectin-dependent leukocyte rolling is a requisite step in this process, we hypothesized that IPC would attenuate postischemic P-selectin expression. To address this postulate, P-selectin expression was evaluated in nonischemic (control) rat jejunum and in rat jejunum subjected to I/R alone (20 min ischemia/60 min reperfusion), or IPC (5 min ischemia/10 min reperfusion) + I/R using a dual radiolabeled monoclonal antibody approach. I/R was associated with a sevenfold increase in jejunal P-selectin expression, an effect that was completely abolished by IPC. Exposing the bowel to adenosine deaminase or an adenosine A1, but not an A2, receptor antagonist during the period of preconditioning ischemia or to selective PKC antagonists during prolonged ischemia prevented the beneficial effect of IPC to limit I/R-induced P-selectin expression. Our data indicate that P-selectin expression is a novel downstream effector target of the adenosine-initiated, PKC-dependent, anti-inflammatory signaling pathway in IPC.
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PMID:Ischemic preconditioning prevents postischemic P-selectin expression in the rat small intestine. 1060 Aug 71

Protein kinase C (PKC) has been implicated in ischemic preconditioning, but whether it plays a role in the cardioprotection observed in the diabetic heart is not known. We assessed the possible role of PKC by investigating whether the inhibition of PKC with staurosporine (Stau, 0.01 microM) or chelerythrine (Chel, 1 microM) can abolish the increased resistance to ischemia (25 min)-reperfusion (30 min) injury in Langendorff perfused hearts from streptozotocin-induced 4-week diabetic rats. In the diabetic heart, pre-ischemic left ventricular developed pressure (LVDP), double product (DP: LVDPxheart rate/1,000), +/- dP/dt(max) and coronary flow rate (CFR) were all reduced compared to the control. The pretreatment with Stau or Chel significantly improved these parameters. The post-ischemic contractile function was recovered to a greater extent in the diabetic heart (116.9 +/- 20.5% of pre-ischemic DP) than in the control (23.3 +/- 2.3% of pre-ischemic DP), indicating the increased resistance of the diabetic heart to ischemia-reperfusion injury. The treatment with Stau or Chel abolished the enhanced recovery in the diabetic heart (36.0 +/- 14.6 and 54.1 +/- 12.8% of pre-ischemic DP, respectively). The reduction in post-ischemic end diastolic pressure (EDP) and lactate dehydrogenase (LDH) release in diabetes (13.5 +/- 2.5 mmHg and 27.2 +/- 6.2 U/g heart) compared to the control (55.8 +/- 2.9 mmHg and 60. 3 +/- 5.7 U/g heart) was significantly (p<0.05) increased by pretreatment with Stau (39.0 +/- 4.9 mmHg and 53.1 +/- 7.6 U/g heart) or Chel (36.2 +/- 3.0 mmHg and 48.8 +/- 4.3 U/g heart). Neither Stau nor Chel had any influence on the post-ischemic values of LVDP, DP, +/- dP/dt(max), EDP and LDH release in the control heart. In the conclusion, the present results suggest that PKC activation may, at least in part, contribute to the increased resistance of the diabetic heart to ischemia-reperfusion injury.
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PMID:Protein kinase C inhibitors abolish the increased resistance of diabetic rat heart to ischemia-reperfusion injury. 1060 24


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