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

The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
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PMID:Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. 277 37

Carnitine palmitoyltransferase-I (CPT-I) inhibitors improve postischemic myocardial function either by decreasing muscle long-chain acylcarnitines (LCAC) during ischemia or by increasing oxidation of alternate substrates such as glucose during reperfusion. These possibilities were evaluated using oxfenicine, a CPT-I inhibitor, and alternate substrates that bypass carnitine-dependent metabolism. Isolated rat hearts subjected to 20 min of ischemia followed by 40 min of reperfusion with 1.8 mM palmitate as exogenous substrate recovered little function during reperfusion. Hearts made ischemic and reperfused with palmitate and 2.4 mM hexanoate as exogenous substrates had significantly improved reperfusion function compared to palmitate-perfused hearts. Addition of 2 mM oxfenicine to palmitate-hexanoate-perfused hearts gave an additional small improvement in reperfusion function. At the end of ischemia, the LCAC content of hearts perfused with palmitate or hexanoate and palmitate was identical. Palmitate-, hexanoate, and oxfenicine-perfused hearts had significantly decreased LCAC content at the end of ischemia compared with hexanoate-palmitate-perfused hearts. Therefore, depressed reperfusion function in long-chain fatty acid-perfused hearts can be ameliorated by alternate substrates, including medium-chain fatty acids. LCAC accumulation during ischemia apparently plays only a minor role in the postischemic dysfunction of long-chain fatty acid-perfused hearts.
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PMID:Acylcarnitine accumulation does not correlate with reperfusion recovery in palmitate-perfused rat hearts. 761 1

The effect of incubation with the protein kinase C activator, 4 beta-phorbol 12,13-dibutyrate (beta-PDBu) on the electrophysiological responses to hypoxia and combined hypoxia and hypoglycemia was investigated in the rat hippocampal slice. Preincubation with beta-PDBu prevents adenosine-mediated inhibition of synaptic transmission under normoxic, normoglycemic conditions. beta-PDBu preincubation also reduces the adenosine-mediated hypoxia-induced depression of synaptic transmission revealing a substantial adenosine-independent hypoxia-induced depression of synaptic transmission. During combined hypoxia and hypoglycemia, slices preincubated in beta-PDBu display a significant shortening of the time of anoxic depolarization, an effect of beta-PDBu that is not mimicked by application of the adenosine antagonist cyclopentyltheophylline (8-CPT). It is concluded that the state of PKC activation may influence the electrophysiological responses to hypoxia and ischemia.
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PMID:Phorbol ester alters the electrophysiological responses to hypoxia and ischemic-like conditions in the rat hippocampal slice. 858 22

von Willebrand factor (vWF) is stored and released from endothelial secretory granules called Weibel-Palade (WP) bodies. Acute release can be induced by thrombin, histamine, and other mediators of thrombosis or inflammation. Their effect is thought to be mediated by an increase in intracellular free calcium ([Ca2+]i). Purine nucleotides such as adenosine triphosphate (ATP) and adenosine diphosphate (ADP) are released from platelet dense granules and from ischemic tissues and are important regulators of platelet function and vascular tone. In the present study, we investigated whether they could also induce exocytosis from cultured endothelial cells. ATP (1 to 100 micromol/L) induced a dose-related increase in vWF release, with a 2.3-fold maximal increase after 30 minutes. Similar responses were observed with ADP. ATP induced calcium mobilization from intracellular stores, an effect mimicked by 2-methylthio-ATP, a selective agonist for P2y receptors. However, 2-methylthio-ATP-induced vWF release was only 43% of the ATP response. ATP-induced vWF release was also associated with a twofold increase in cellular cyclic adenosine monophosphate (cAMP) content, and was potentiated by 3-isobutyl-1-methylxanthine ([IBMX] added to increase cAMP levels by blocking cellular phosphodiesterases) and 8-bromo-cAMP and inhibited by more than 50% by Rp-8-CPT-cAMPS, a competitive protein kinase A inhibitor. Adenosine but not 2-methylthio-ATP mimicked the ATP-induced increase in cAMP. ATP-induced vWF release was partly inhibited by adenosine deaminase, which degrades adenosine generated from ATP in the incubation medium. Adenosine (1 to 100 micromol/L) failed to induce vWF release, but potentiated the secretory response to 2-methylthio-ATP and thrombin without modifying the calcium response to these agents. Our results suggest that ATP/ADP can induce vWF release from endothelial cells via dual activation of P2y and adenosine A2 receptors. ATP/ADP-induced exocytosis could be involved in the regulation of thrombus formation and ischemia-reperfusion injuries. Further, we provide evidence that a receptor-mediated increase in cellular cAMP can potentiate the secretory response to calcium-mobilizing agents.
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PMID:Purine nucleotides induce regulated secretion of von Willebrand factor: involvement of cytosolic Ca2+ and cyclic adenosine monophosphate-dependent signaling in endothelial exocytosis. 941 75

Adenosine kinase (AK) inhibitors potentiate the actions of endogenous adenosine (ADO) and ameliorate cerebral ischemic damage in animal models. The present study examined the effects of the AK inhibitor, 5-iodotubercidin (5-IT) in an in vitro model of neuronal ischemia, specifically, combined oxygen-glucose deprivation of rat cortical mixed neuronal-glial cultures. Oxygen-glucose deprivation caused extensive neuronal loss which was accompanied by a marked increase in ADO release into the extracellular medium, was ameliorated by exogenous ADO (10 microM(-1) mM), and was exacerbated by a high concentration of the selective A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 10 microM). 5-IT (1 microM) had no effect on extracellular ADO levels nor on neuronal loss. However, AK activity in these cultures was markedly suppressed during oxygen-glucose deprivation. Taken together, these data demonstrate a marked down-regulation of AK activity during oxygen-glucose deprivation in this in vitro model, providing an endogenous mechanism contributing to the accumulation of extracellular ADO, which exerts neuroprotective effects by activating the ADO A1 receptor.
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PMID:Inhibition of adenosine kinase during oxygen-glucose deprivation in rat cortical neuronal cultures. 973 97

The mechanisms underlying the depression of evoked fast excitatory postsynaptic currents (EPSCs) following superfusion with medium deprived of oxygen and glucose (in vitro ischemia) for a 4-min period in hippocampal CA1 neurons were investigated in rat brain slices. The amplitude of evoked fast EPSCs decreased by 85 +/- 7% of the control 4 min after the onset of in vitro ischemia. In contrast, the exogenous glutamate-induced inward currents were augmented, while the spontaneous miniature EPSCs obtained in the presence of tetrodotoxin (TTX, 1 microM) did not change in amplitude during in vitro ischemia. In a normoxic medium, a pair of fast EPSCs was elicited by paired-pulse stimulation (40-ms interval), and the amplitude of the second fast EPSC increased to 156 +/- 24% of the first EPSC amplitude. The ratio of paired-pulse facilitation (PPF ratio) increased during in vitro ischemia. Pretreatment of the slices with adenosine 1 (A1) receptor antagonist, 8-cyclopenthyltheophiline (8-CPT) antagonized the depression of the fast EPSCs, in a concentration-dependent manner: in the presence of 8-CPT (1-10 microM), the amplitude of the fast EPSCs decreased by only 20% of the control during in vitro ischemia. In addition, 8-CPT antagonized the enhancement of the PPF ratio during in vitro ischemia. A pair of presynaptic volleys and excitatory postsynaptic field potentials (fEPSPs) were extracellularly recorded in a proximal part of the stratum radiatum in the CA1 region. The PPF ratio for the fEPSPs also increased during in vitro ischemia. On the other hand, the amplitudes of the first and second presynaptic volley, which were abolished by TTX (0.5 microM), did not change during in vitro ischemia. The maximal slope of the Ca(2+)-dependent action potential of the CA3 neurons, which were evoked in the presence of 8-CPT (1 microM), nifedipine (20 microM), TTX (0.5 microM), and tetraethyl ammonium chloride (20 mM), decreased by 12 +/- 6% of the control 4 min after the onset of in vitro ischemia. These results suggest that in vitro ischemia depresses the evoked fast EPSCs mainly via the presynaptic A1 receptors, and the remaining 8-CPT-resistant depression of the fast EPSCs is probably due to a direct inhibition of the Ca(2+) influx to the axon terminals.
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PMID:Mechanisms underlying the depression of evoked fast EPSCs following in vitro ischemia in rat hippocampal CA1 neurons. 1153 60

Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 microM resveratrol; 3) 10 microM resveratrol + 1 microM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A(1) receptor blocker); 4) 10 microM resveratrol + 1 microM 8-(3-chlorostyryl)caffeine (CSC; adenosine A(2a) receptor blocker); 5) 10 microM resveratrol + 1 microM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A(3) receptor blocker); or 6) 10 microM resveratrol + 3 microM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A(1) and A(3) receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A(1) and A(3) receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.
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PMID:Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. 1534 77

Ischemic preconditioning (IP) triggers cardioprotection via a signaling pathway that converges on mitochondria. The effects of the inhibition of carnitine palmitoyltransferase I (CPT-I), a key enzyme for transport of long chain fatty acids (LCFA) into the mitochondria, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated, in isolated perfused rat hearts, whether sub-chronic CPT-I inhibition (5 days i.p. injection of 25 mg/kg/day of Etomoxir) affects I/R-induced damages and whether cardioprotection by IP can be induced after this inhibition. Effects of global ischemia (30 min) and reperfusion (120 min) were examined in hearts harvested from Control (untreated), Vehicle- or Etomoxir-treated animals. In subsets of hearts from the three treated groups, IP was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each condition was assessed by changes in infarct size as well as in myocardial contractility. Postischemic contractility, as indexed by developed pressure and dP/dt(max), was similarly affected by I/R, and was similarly improved with IP in Control, Vehicle or Etomoxir treated animals. Infarct size was also similar in the three subsets without IP, and was significantly reduced by IP regardless of CPT-I inhibition. We conclude that CPT-I inhibition does not affect I/R damages. Our data also show that IP affords myocardial protection in CPT-I inhibited hearts to a degree similar to untreated animals, suggesting that a long-term treatment with the metabolic anti-ischemic agent Etomoxir does not impede the possibility to afford cardioprotection by ischemic preconditioning.
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PMID:Myocardial protection from ischemic preconditioning is not blocked by sub-chronic inhibition of carnitine palmitoyltransferase I. 1591 95

The rate of cardiac fatty acid oxidation is regulated by the activity of carnitine palmitoyltransferase-I (CPT-I), which is inhibited by malonyl-CoA. We tested the hypothesis that the activity of the enzyme responsible for malonyl-CoA degradation, malonyl-CoA decarboxlyase (MCD), regulates myocardial malonyl-CoA content and the rate of fatty acid oxidation during demand-induced ischemia in vivo. The myocardial content of malonyl-CoA was increased in anesthetized pigs using a specific inhibitor of MCD (CBM-301106), which we hypothesized would result in inhibition of CPT-I, reduction in fatty acid oxidation, a reciprocal activation of glucose oxidation, and diminished lactate production during demand-induced ischemia. Under normal-flow conditions, treatment with the MCD inhibitor significantly reduced oxidation of exogenous fatty acids by 82%, shifted the relationship between arterial fatty acids and fatty acid oxidation downward, and increased glucose oxidation by 50%. Ischemia was induced by a 20% flow reduction and beta-adrenergic stimulation, which resulted in myocardial lactate production. During ischemia MCD inhibition elevated malonyl-CoA content fourfold, reduced free fatty acid oxidation rate by 87%, and resulted in a 50% decrease in lactate production. Moreover, fatty acid oxidation during ischemia was inversely related to the tissue malonyl-CoA content (r = -0.63). There were no differences between groups in myocardial ATP content, the activity of pyruvate dehydrogenase, or myocardial contractile function during ischemia. Thus modulation of MCD activity is an effective means of regulating myocardial fatty acid oxidation under normal and ischemic conditions and reducing lactate production during demand-induced ischemia.
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PMID:Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia. 1610 Feb 46

The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.
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PMID:Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. 1630 12


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