Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that heat-shock proteins (HSPs) mediate delayed cardioprotection of prior kappa-opioid receptor (kappa-OR) stimulation, we first correlated cellular injury and viability with the expression of HSP70s in isolated rat ventricular myocytes subjected to prior kappa-OR stimulation with the selective agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U-50488H) and delayed lethal simulated ischemia (LSI). Cell injury and viability were indicated by lactate dehydrogenase release and trypan blue exclusion, respectively. The reduced injury and increased viability after pretreatment with U-50488H were concentration dependent and correlated directly with the expression of both stress-inducible (HSP70) and constitutive (HSC70) proteins. The effects mimic those with metabolic inhibition preconditioning (MIP). The cardioprotection against LSI by pretreatment with U-50488H and MIP was abolished and antagonized, respectively, via blockade of the kappa-OR by its selective antagonist, nor-binaltorphimine. We also found that blockade of the production of HSP70 but not HSC70 blocked the inhibitory effect of pretreatment with U-50488H on injury and viability. These observations provide evidence that stress-inducible HSP70 mediates delayed cardioprotection of prior kappa-OR stimulation.
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PMID:Inducible HSP70 mediates delayed cardioprotection via U-50488H pretreatment in rat ventricular myocytes. 1140 66

Opioids have been shown to produce both an early and delayed phase of cardioprotection; however, the signaling pathways involved, particularly in the delayed response, have not been well defined. Therefore, we investigated the potential of BW373U86 (BW), a potent delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors and oxygen-derived free radicals (OFRs) in this delayed response. All rats underwent 30 min of ischemia followed by 2 h of reperfusion. The rats were divided into four groups. First, rats were pretreated with selective opioid receptor antagonists or the antioxidant, 2-mercaptopropionyl glycine (2-MPG), in the presence of BW and allowed to recover for 24 h before the ischemia-reperfusion protocol. Second, rats were pretreated with BW, allowed to recover for 24 h, and subsequently treated with either opioid antagonists or 2-MPG, 10 min prior to the ischemia-reperfusion protocol. Third, rats underwent ischemic preconditioning (IPC) (1x5 min occlusion) both with and without 2-MPG to determine the role of OFRs in acute cardioprotection. Fourth, rats were pretreated with TAN-67, an opioid agonist known to signal through the delta1 opioid receptor in the presence and absence of 2-MPG. Control rats were injected with saline and allowed to recover for 24 h. BW produced a bell-shaped dose-related reduction in infarct size with a maximal reduction observed at 0.1 mg/kg v control (16+/-3%v 60+/-3%, P<0.001). Surprisingly, the delayed protection induced by BW was only partially blocked by pretreatment with the delta1-selective antagonist, BNTX; however, it was completely blocked by pretreatment with 2-MPG (47+/-5%, P<0.001). Only naloxone given acutely inhibited the protective effects of BW; however, at the dose used, 2-MPG partially reduced the protective effect of acute IPC. TAN-67 (0.1 mg/kg) also produced a significant reduction in infarct size compared to control (18+/-4%v 60+/-3%, P<0.001). This protection was blocked by pretreatment with 2-MPG (42+/-4%, P<0.001). These data suggest that BW and TAN-67 mediate delayed cardioprotection via a free radical mechanism that appears to be only partially dependent on delta opioid receptor stimulation. Furthermore, it is the early burst in OFRs that is crucial to initiating the protective effect.
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PMID:BW373U86, a delta opioid agonist, partially mediates delayed cardioprotection via a free radical mechanism that is independent of opioid receptor stimulation. 1144 28

Stress-activated protein kinases may be essential to cardioprotection. We assessed the role of p38 in an in vivo rat model of ischemia-reperfusion. Ischemic preconditioning (IPC) and the delta(1)-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-octahydroquinolino [2,3,3-g]isoquinoline (TAN-67) significantly reduced infarct size (IS), expressed as a percentage of the area at risk (AAR), versus animals subjected only to 30 min of ischemia and 2 h of reperfusion (7.1 +/- 1.5 and 29.6 +/- 3.3 vs. 59.7 +/- 1.6%). The p38 antagonist SB-203580 attenuated IPC when it was administered before (34.0 +/- 6.9%) or after (25.0 +/- 3.8%) the IPC stimulus; however, it did not significantly attenuate TAN-67-induced cardioprotection (39.6 +/- 3.2). We also assessed the phosphorylation of p38 and c-jun NH(2)-terminal kinase (JNK) throughout ischemia-reperfusion in nuclear and cytosolic fractions. After either intervention, no increase was detected in the phosphorylation state of either enzyme in the nuclear fraction or for p38 in the cytosolic fraction versus control hearts. However, there was a robust increase in JNK activity in the cytosolic fraction immediately on reperfusion that was more pronounced in animals subjected to IPC or administered TAN-67. These data suggest that SB-203580 likely attenuates IPC via the inhibition of kinases other than p38, which may include JNK. The data also suggest that activation of JNK during early reperfusion may be an important component of cardioprotection.
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PMID:Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium. 1151 86

We have shown that the cardioprotective benefits of ischemic preconditioning (PC) can be transferred from PC to virgin acceptor hearts via coronary effluent transfusion, implicating the presence of hormonal preconditioning factor(s). Using isolated buffer-perfused rabbit hearts, our aims were to: (1) determine whether the protective factor(s) could be concentrated and recovered by reverse phase chromatography and (2) whether opioid receptor activation contributes to this transferred cardioprotection. Material released into the coronary effluent during PC ischemia/reperfusion or normoxic perfusion was concentrated by reverse phase chromatography. In phase one, hearts received no intervention (controls), PC ischemia, concentrate generated from normoxic hearts (normoxic acceptors) or concentrate from PC hearts (PC acceptors). All hearts underwent 40 min of global ischemia, and area of necrosis (AN) was delineated by tetrazolium staining. In phase two, three additional groups of hearts (control, PC and PC acceptors) received the opioid antagonist naloxone (2 microM) throughout the intervention phase. Treatment with normoxic concentrate had no effect on infarct size: (AN: normoxic acceptors 39+/-8%; control 42+/-8%). In contrast, treatment with PC concentrate evoked cardioprotection equivalent to that afforded by conventional PC (AN 19+/-5% and 21+/-6% respectively P<0.05 v control). Naloxone had no effect on infarct size in controls, and did not inhibit preconditioning. However, naloxone abrogated the protection achieved by transfer of PC concentrate (AN: 44+/-7%). These results indicate that PC concentrate evokes a cardioprotective effect via a mechanism requiring an intact opioid receptor system.
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PMID:Naloxone blocks transferred preconditioning in isolated rabbit hearts. 1154 53

It has been found that after intravenous administration of selective agonist of mu-opioid receptors DAGO (0.1 mg/kg 15 min before heart excision) isolated rat heart becomes resistant to ischemia (45 min) and reperfusion (60 min) ex vivo. The in vivo pretreatment with DAGO prevented reperfusion injury of cardiac cells and decreased myocardial content of conjugated dienes during ischemia and reperfusion of the heart in vitro. In addition, similar mu-opioid receptor stimulation promotes a postischemic recovery of myocardial contractility in the postischemic period. However, this receptor activation does not affect heart tolerance to free radical damage during perfusion of isolated heart by a solution containing Fe(2+)-ascorbic acid.
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PMID:[Activation of mu-opioid receptors and cardiomyocyte resistance to free radical damage]. 1155 Mar 61

It is demonstrated that intravenous administration of the kappa 1-opioid receptor (OR) agonists (-)-trans-(1S,S)-U-50,488 and (+)-trans-(1R,2R)-U-50,488 increases heart tolerance to the arrhythmogenic effect of epinephrine in rats. This antiarrhythmic effect was completely abolished by preliminary kappa-OR blocking with norbinaltorphimine. Preliminary administration of of a high-affinity kappa 1-OR agonist (-)-trans-(1S,S)-U-50,488 significantly reduced the incidence of ventricular arrhythmias upon coronary artery occlusion and reperfusion in vivo. The low-affinity (+)-trans-(1R,2R)-U-50,488 does not show antiarrhythmic activity under ischemia and reperfusion of myocardium. It is concluded that the antiarrhythmic action of kappa 1-OR agonists in the adrenal, ischemic, and reperfusion arrhythmia models has a receptor-specific character.
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PMID:[Specificity of the anti-arrhythmic effect of kappa1-opioid receptor agonists]. 1158 1

We investigated the possibility that opioids activate a tyrosine kinase (TK) that mediates cardioprotection in an in vivo rat model of myocardial infarction. All animals underwent 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk (IS/AAR). Control animals had an IS/AAR of 58.2 +/- 0.6. Cardioprotection was induced with the delta1- or delta1/delta2-selective opioid agonists, TAN-67, or D-Ala D-Leu enkephalin (DADLE). Both significantly reduced IS/AAR (28.8 +/- 3.6 and 34.8 +/- 3.8, respectively). The general TK inhibitor, genistein, abolished cardioprotection produced by TAN-67 or DADLE (59.1 +/- 3.2 and 61.5 +/- 3.4, respectively), whereas the structural analog, daidzein, lacking TK inhibitory activity, did not. Interestingly, the selective Src/epidermal growth factor (EGF) receptor TK inhibitor, lavendustin A, did not abolish TAN-67-induced cardioprotection (22.1 +/- 6.8). Similarly, the Src-selective TK antagonist, PP2, had no effect on DADLE-induced cardioprotection (31.1 +/- 7.3). These unexpected findings suggest that Src and EGF receptor TKs are not important in the genesis of cardioprotection produced by TAN-67. Finally, we demonstrate that genistein did not affect protein kinase C (PKC) translocation induced by TAN-67. These data suggest that a TK, but most likely not an Src/EGF receptor TK, is important in cardioprotection via opioid receptor stimulation and that the pathway for TK activation is downstream from or parallel to PKC activation in the in situ rat heart since genistein could not affect PKC translocation of selective isoforms induced by TAN-67 and assessed by immunohistochemistry.
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PMID:Dependence of delta1-opioid receptor-induced cardioprotection on a tyrosine kinase-dependent but not a Src-dependent pathway. 1160 57

Kappa-opioid receptor (OR) stimulation with a selective agonist, U50,488H (U50), known to mediate the delayed cardioprotection of metabolic inhibition preconditioning (MIP) against cell injury/death in rat ventricular myocytes, has been shown to act via protein kinase C (PKC). We attempted to identify the PKC isoform(s) that is activated, thus triggering delayed cardioprotection of MIP and pretreatment with 10 microM U50 (U50 pretreatment, UP). Release of lactate dehydrogenase and exclusion of trypan blue by isolated rat ventricular myocytes were used as indices of cell injury and death, respectively. Both MIP and UP induced translocation of PKC-epsilon, but not other PKC isoforms, -alpha and -delta, from cytosolic to membrane fractions. This was accompanied by reductions in cell injury/death induced by lethal simulated ischemia. The effects of MIP and UP were attenuated and abolished by 1 microM nor-binaltorphimine, a selective kappa-OR antagonist, administered before and during preconditioning/pretreatment, respectively. The effects were mimicked by 10 nM phorbol-12-myristate-13-acetate, a PKC activator, but attenuated by 5 microM chelerythrine, a PKC inhibitor. More importantly, 0.1 microM epsilonV1-2, a selective PKC-epsilon inhibitor administered before and during MIP/UP, also attenuated the effects of both treatments on cell injury/death and translocation of PKC-epsilon. On the other hand, 5 microM rottlerin, a selective PKC-delta inhibitor, did not alter the effects of either treatment on injury/death. The results indicate that both MIP and UP activate PKC-epsilon, leading to delayed cardioprotection in rat ventricular myocytes.
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PMID:Protein kinase C-epsilon is a trigger of delayed cardioprotection against myocardial ischemia of kappa-opioid receptor stimulation in rat ventricular myocytes. 1160 72

Preliminary administration of the mu-opioid receptor (mu-OR) agonist DAMGO (0.1 mg/kg) 15 min before heart isolation led to attenuation of the postischemic systolic and diastolic contractility dysfunction in isolated perfused rat heart. In addition, the mu-OR decreased creatine kinase (CK) release from the heart during the postischemic period, which was indicative of an increase in the sarcolemma tolerance to reperfusion injury. This protective effects are mediated by KATP channel activation. These data show that the mu-OR stimulation in vivo increases, by means of the KATP channel activation, the cardiac tolerance to the ischemia and reperfusion injury in vitro. Pretreatment with mu-OR agonists DAMGO or DALDA in vitro (0.5 mg/liter, 15 min prior to ischemia) exacerbated the postischemic contractility dysfunction of myocardium and did not affect the CK release. It is concluded that the protective effect of mu-OR simulation in vivo is mediated by the activation of these receptors localized outside the heart, probably with an unknown circulating humoral factor.
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PMID:[Participation of K(ATP)-channels in cardioprotective effect of mu-opioid receptor agonists in acute ischemia and reperfusion of the isolated heart]. 1176 93

We examined whether pharmacological inhibition of glycogenolysis by N-methyl-1-deoxynojirimycin (MOR-14), a new compound which reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase activity of the glycogen-debranching enzyme, can protect the heart against postischemic left ventricular dysfunction. The hearts of male Sprague-Dawley rats were excised, and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during the ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s), and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min including a 30-min preischemic period followed by a 30-min episode of global ischemia and 60 min reperfusion. with or without 0.5 or 2 mM of MOR-14 during the 30-min preischemic period or the first 30 min of reperfusion. In another series of experiments, the myocardial content of glycogen and lactate was measured during the 30-min episode of ischemia in groups treated with and without 2mM of MOR-14. Preischemic but not postischemic treatment with MOR-14 significantly improved LVDP and +/-dP/dt without altering coronary flow during reperfusion in a dose-dependent manner. MOR-14 significantly preserved the glycogen content and significantly attenuated the lactate accumulation during the 30-min episode of ischemia. Preischemic treatment with MOR-14 is protective against postischemic left ventricular dysfunction through the inhibition of glycogenolysis in the isolated rat heart.
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PMID:N-methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, markedly improves postischemic left ventricular dysfunction. 1176 64


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