Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.
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PMID:Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation. 1661 6

Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that delta-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K(+), which plays a role in neuronal death, we asked whether DOR activation preserves K(+) homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K(+)-sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala(2), D-Leu(5)]-enkephalinamide attenuated the anoxia- and OGD-induced increase in extracellular K(+) and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K(+) and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K(+) homeostasis. These data suggest that activation of DOR protects the cortex against anoxia- or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K(+) homeostasis during anoxia or ischemia.
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PMID:Cortical delta-opioid receptors potentiate K+ homeostasis during anoxia and oxygen-glucose deprivation. 1677 40

Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.
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PMID:Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning. 1679 12

Data on the antiarrhythmic properties of opioid receptor (OR) agonists have been systematized. An analysis of published works which indicate that opioids increase cardiac tolerance to arrhythmogenic influences both in vivo and in vitro has been performed. For example, occupancy of central micro- and delta-OR and also ORL1 receptors increases cardiac tolerance to arrhythmogenic action epinephrine and aconitine. In contrast, activation of central kapa-OR exacerbates arrhythmogenic action epinephrine. Stimulation of peripheral delta2- and kappa1-OR decreases an incidence of arrhythmias induced coronary artery occlusion and reperfusion in vivo. Occupancy of peripheral micro-, kappa2-, delta1-OR and also ORL1 receptors has no effect on the cardiac tolerance to arrhythmogenic action of ischemia and reperfusion but increases cardiac electrical stability in rats with post-infarction cardiosclerosis. Authors suggest that opioids which unable penetrate to blood barrier may be used for therapy of arrhythmias.
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PMID:[Antiarrhythmic properties of opioid receptor agonists]. 1699 44

We tested the hypothesis that the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) improves recovery from myocardial stunning. Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic and left ventricular pressure (LVP), and the maximum rate of LVP increase (LV dP/dt(max)) and decrease (LV dP/dt(max)), coronary blood flow velocity and myocardial wall-thickening fraction. Regional myocardial blood flow was determined with fluorescent microspheres. Catecholamine plasma levels were measured by high-performance liquid chromatography, and beta-endorphin and dynorphin plasma levels by radioimmunoassay. An occluder around the left anterior descending artery (LAD) allowed induction of a reversible LAD-ischemia. Animals underwent two experiments in a randomized crossover fashion on separate days: (a) 10 min LAD-occlusion (control experiment), (b) second ischemic episode 24 h after nor-BNI (2.5 mg/kg IV) (intervention). Dogs receiving nor-BNI showed an increase in wall-thickening fraction, LV dP/dt(max) and LV dP/dt(min) before ischemia and during the whole reperfusion (P < 0.05 versus control experiment). After nor-BNI pretreatment, dynorphin levels increased after induction of ischemia to a peak level of 15.1 +/- 3.6 pg/mL (P < 0.05 versus control experiment). The increase in plasma beta-endorphin during ischemia and early reperfusion was attenuated after nor-BNI. Compared with the control experiment, nor-BNI left global hemodynamics, regional myocardial blood flow, and catecholamine levels unchanged. In conclusion, nor-BNI improves recovery from myocardial stunning after regional myocardial ischemia in chronically instrumented dogs.
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PMID:Kappa-opioid receptor antagonism improves recovery from myocardial stunning in chronically instrumented dogs. 1700 Jul 88

We have shown that exposure of neurons to opioid immediately before ischemia induces ischemia tolerance. This phenomenon is called acute opioid preconditioning. In this study, we test the hypothesis that opioids induce delayed neuropreconditioning (from hours to days after opioid exposure). Exposure to morphine, an agonist for delta-, mu-, and kappa-opioid receptors, or Tan-67, a selective delta1-receptor agonist, for 30 minutes at 24 hours before a 35-minute oxygen-glucose deprivation (OGD, to simulate ischemia in vitro) dose-dependently reduced the OGD-induced neuronal death in the CA1 region of the rat organotypic hippocampal slice cultures. The morphine preconditioning-induced neuroprotection was inhibited by beta-funaltrexamine, a mu-opioid receptor antagonist, but not by 7-benzylidenenaltrexone, a delta1-receptor antagonist, or nor-binaltorphimine, a kappa-receptor antagonist. The Tan-67 preconditioning-induced neuroprotection was inhibited by 7-benzylidenenaltrexone. The combination of morphine and Tan-67 did not induce a better preconditioning effect than did morphine or Tan-67 alone. Application of morphine and Tan-67 at 24 hours before permanent right middle cerebral arterial occlusion reduced brain infarct volume and improved neurologic functional outcome assessed 24 hours after the occlusion in adult male rats. These results suggest that morphine and Tan-67 induce a delayed preconditioning effect in the brain under in vivo and in vitro conditions. Whereas the delayed phase of morphine preconditioning may involve mu-opioid receptors, Tan-67 preconditioning may be mediated by delta1-opioid receptors. Morphine and Tan-67 may activate a shared intracellular signaling pathway to induce the delayed preconditioning effects in the brain.
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PMID:Opioid preconditioning induces opioid receptor-dependent delayed neuroprotection against ischemia in rats. 1702 99

In the present study, we determined whether interleukin-2 (IL-2) confers cardioprotection by inhibiting mitochondria permeability transition pore (MPTP) opening. In isolated rat hearts subject to 30 min ischemia and 120 min reperfusion (IR), IL-2 (50 U/ml) decreased the infarct size and LDH release, effects blocked by a selective kappa-opioid receptor antagonist, Nor-BNI (5 microM) or an opener of MPTP, atractyloside (Atr, 20 microM). In isolated ventricular myocytes subjected to anoxia and reoxygenation (AR), which reduced both the amplitude of the electrically induced [Ca2+]i transient and diastolic [Ca2+]i, IL-2 attenuated the AR-induced alterations and their effects were abolished by Atr. In addition, IL-2 attenuated the reduction in calcein fluorescence in myocytes subject to AR and reduced calcium-induced swelling in mitochondria of rat hearts subjected to IR, which were similar to effect of inhibitor of MPTP. The observations indicated that IL-2 confers cardioprotection by inhibiting the MPTP opening.
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PMID:Interleukin-2 confers cardioprotection by inhibiting mitochondrial permeability transition pore. 1727 Oct 75

Two series of experiments were performed in the perfused isolated rat heart to determine whether stimulation of &#954;-opioid receptor with U50,488H, a selective &#954;-opioid receptor agonist, produces any changes in electrical coupling during prolonged ischemia and whether these changes in electrical coupling is associated with the cardioprotection induced by U50,488H. It was found that U50,488H concentration dependently increased formazan content and reduced lactate dehydrogenase (LDH) release induced by 30 min of ischemia and 120 min of reperfusion, and the ameliorating effect of 10^-5mol/L U50,488H was abolished by 5x10^-6mol/L nor-binaltorphimine (nor-BNI), a selective &#922;-opioid receptor antagonist, or 10^-4mol/L 5-hydroxydecanoate (5-HD), a selective mitochondrial ATP-sensitive K⁺(K<inf>ATP</inf>) channels blocker. The onset of electrical uncoupling during prolonged ischemia was delayed by U50,488H, and delaying effect was not only abolished, but also advanced by nor-BNI or 5-HD compared with control group. These results demonstrate that delayed electrical uncoupling is associated with the cardioprotection induced by U50,488H. These effects of U50,488H are mediated by mitochondrial K<inf>ATP</inf>channels.
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PMID:The Effects of &#954;-Opioid Receptor Stimulation on Electrical Coupling during Ischemia in the Perfused Isolated Rat Heart. 1728 27

It is shown that prestimulation of cardiac delta-opioid receptors (OR) by selective agonists (DPDPE and TAN-67) decreases creatine kinase levels in the coronary effluent of isolated rat heart during 45-min global ischemia and 30-min reperfusion. This effect was completely abolished by pretreatment with a delta-antagonist naltrindole or a non-selective agonist naloxone. It was found that preactivation of cardiac delta-OR exacerbates reperfusion contractility dysfunction of the heart. This effect was also eliminated by opioid receptor antagonists. It is suggested that stimulation of cardiac delta-OR prevents irreversible cardiac cell damage but exacerbates contractility dysfunction during ischemia and reperfusion in vitro.
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PMID:[Delta-opioid receptor activation prevents appearance of irreversible damages of cardiomyocytes and exacerbates myocardial contractility dysfunction during ischemia and reperfusion]. 1730 82

Transient global ischemia is a neuronal insult that induces delayed, selective death of hippocampal CA1 pyramidal neurons. A mechanism underlying ischemia-induced cell death is activation of the gene silencing transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor) and REST-dependent suppression of the AMPA receptor subunit GluR2 in CA1 neurons destined to die. Here we show that REST regulates an additional gene target, OPRM1 (mu opioid receptor 1 or MOR-1). MORs are abundantly expressed by basket cells and other inhibitory interneurons of CA1. Global ischemia induces a marked decrease in MOR-1 mRNA and protein expression that is specific to the selectively vulnerable area CA1, as assessed by quantitative real-time RT-PCR, Western blotting, and ChIP. We further show that OPRM1 gene silencing is REST-dependent and occurs via epigenetic modifications. Ischemia promotes deacetylation of core histone proteins H3 and H4 and dimethylation of histone H3 at lysine-9 (H3-K9) over the MOR-1 promoter, an signature of epigenetic gene silencing. Acute knockdown of MOR-1 gene expression by administration of antisense oligodeoxynucleotides to hippocampal slices in vitro or injection of the MOR antagonist naloxone to rats in vivo affords protection against ischemia-induced death of CA1 pyramidal neurons. These findings implicate MORs in ischemia-induced death of CA1 pyramidal neurons and document epigenetic remodeling of expression of OPRM1 in CA1 inhibitory interneurons.
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PMID:Ischemic insults promote epigenetic reprogramming of mu opioid receptor expression in hippocampal neurons. 1736 Apr 95


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