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)

Mitochondrial membrane potential (DeltaPsi(m)) is severely compromised in the myocardium after ischemia-reperfusion and triggers apoptotic events leading to cell demise. This study tests the hypothesis that mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel activation prevents the collapse of DeltaPsi(m) in myocytes during anoxia-reoxygenation (A-R) and is responsible for cell protection via inhibition of apoptosis. After 3-h anoxia and 2-h reoxygenation, the cultured myocytes underwent extensive damage, as evidenced by decreased cell viability, compromised membrane permeability, increased apoptosis, and decreased ATP concentration. Mitochondria in A-R myocytes were swollen and fuzzy as shown after staining with Mito Tracker Orange CMTMRos and in an electron microscope and exhibited a collapsed DeltaPsi(m), as monitored by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Cytochrome c was released from mitochondria into the cytosol as demonstrated by cytochrome c immunostaining. Activation of mitoK(ATP) channel with diazoxide (100 micromol/l) resulted in a significant protection against mitochondrial damage, ATP depletion, cytochrome c loss, and stabilized DeltaPsi(m). This protection was blocked by 5-hydroxydecanoate (500 micromol/l), a mitoK(ATP) channel-selective inhibitor, but not by HMR-1098 (30 micromol/l), a putative sarcolemmal K(ATP) channel-selective inhibitor. Dissipation of DeltaPsi(m) also leads to opening of mitochondrial permeability transition pore, which was prevented by cyclosporin A. The data support the hypothesis that A-R disrupts DeltaPsi(m) and induces apoptosis, which are prevented by the activation of the mitoK(ATP) channel. This further emphasizes the therapeutic significance of mitoK(ATP) channel agonists in the prevention of ischemia-reperfusion cell injury.
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PMID:Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential. 1151

The novel sulfonylthiourea 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR 1883), a blocker of ATP-sensitive K(+) channels (K(ATP) channels), has potential against ischemia-induced arrhythmias. Here, the interaction of HMR 1883 with sulfonylurea receptor (SUR) subtypes and recombinant K(ATP) channels is compared with that of the standard sulfonylurea, glibenclamide, in radioligand receptor binding and electrophysiological experiments. HMR 1883 and glibenclamide inhibited [(3)H]glibenclamide binding to SUR1 with K(i) values of 63 microM and 1.5 nM, and [(3)H]opener binding to SUR2A/2B with K(i) values of 14/44 microM and 0.5/2.8 microM, respectively (values at 1 mM MgATP). The interaction of HMR 1883 with the SUR2 subtypes was more sensitive to inhibition by MgATP and MgADP than that of glibenclamide. In inside-out patches and in the absence of nucleotides, HMR 1883 inhibited the recombinant K(ATP) channels from heart (Kir6.2/SUR2A) and nonvascular smooth muscle (Kir6.2/SUR2B) with IC(50) values of 0.38 and 1.2 microM, respectively; glibenclamide did not discriminate between these channels (IC(50) approximately 0.026 microM). In whole cells, the recombinant vascular K(ATP) channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC(50) values of 5.3 and 0.043 microM, respectively. The data show that the sulfonylthiourea exhibits a selectivity profile quite different from that of glibenclamide with a major loss of affinity toward SUR1 and slight preference for SUR2A. The stronger inhibition by nucleotides of HMR 1883 binding to SUR2 (as compared with glibenclamide) makes the sulfonylthiourea an interesting tool for further investigation.
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PMID:Interaction of the sulfonylthiourea HMR 1833 with sulfonylurea receptors and recombinant ATP-sensitive K(+) channels: comparison with glibenclamide. 1171 94

B-type natriuretic peptide (BNP) has been reported to be released from the myocardium during ischemia. We hypothesized that BNP mediates cardioprotection during ischemia-reperfusion and examined whether exogenous BNP limits myocardial infarction and the potential role of ATP-sensitive potassium (K(ATP)) channel opening. Langendorff-perfused rat hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. The control infarct-to-risk ratio was 44.8 +/- 4.4% (means +/- SE). BNP perfused 10 min before ischemia limited infarct size in a concentration-dependent manner, with maximal protection observed at 10(-8) M (infarct-to-risk ratio: 20.1 +/- 5.2%, P < 0.01 vs. control), associated with a 2.5-fold elevation of myocardial cGMP above the control value. To examine the role of K(ATP) channel opening, glibenclamide (10(-6) M), 5-hydroxydecanoate (5-HD; 10(-4) M), or HMR-1098 (10(-5) M) was coperfused with BNP (10(-8) M). Protection afforded by BNP was abolished by glibenclamide or 5-HD but not by HMR-1098, suggesting the involvement of putative mitochondrial but not sarcolemmal K(ATP) channel opening. We conclude that natriuretic peptide/cGMP/K(ATP) channel signaling may constitute an important injury-limiting mechanism in myocardium.
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PMID:B-type natriuretic peptide limits infarct size in rat isolated hearts via KATP channel opening. 1252 30

To examine the receptor specificity and the mechanism of opioid peptide-induced protection, we examined freshly isolated adult rabbit cardiomyocytes subjected to simulated ischemia. Cell death as a function of time was assessed by trypan blue permeability. Dynorphin B (DynB) and Met5-enkephalin (ME) limitation of cell death (expressed as area under the curve) was sensitive to blockade by naltrindole (NTI, a delta-selective antagonist) and 5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinan (GNTI dihydrochloride, a kappa-selective antagonist): 85.7 +/- 2.7 and 142.9 +/- 2.7 with DynB and DynB + NTI, respectively (P < 0.001), 94.1 +/- 4.2 and 164.5 +/- 7.3 with DynB and DynB + GNTI, respectively (P < 0.001), 111.9 +/- 7.0 and 192.1 +/- 6.4 with ME and ME + NTI, respectively (P < 0.001), and 120.2 +/- 4.3 and 170.0 +/- 3.3 with ME and ME + GNTI, respectively (P < 0.001). Blockade of ATP-sensitive K+ channels eliminated DynB- and ME-induced protection: 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01); 189.6 +/- 5.4 and 139.0 +/- 5.4 for control and ME, respectively (P < 0.001), and 210 +/- 5.9 and 195 +/- 6.1 for 5-HD and ME + 5-HD, respectively (P < 0.001); and 136.0 +/- 5.7 and 63.4 +/- 5.4 for control and ME, respectively (P < 0.001), and 144.6 +/- 4.5 and 114.6 +/- 7.7 for HMR-1098 and ME + HMR-1098, respectively (P < 0.01). We conclude that opioid peptide-induced cardioprotection is mediated by delta- and kappa-receptors and involves sarcolemmal and mitochondrial ATP-sensitive K+ channels.
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PMID:Activation of delta- and kappa-opioid receptors by opioid peptides protects cardiomyocytes via KATP channels. 1273 57

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.
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PMID:Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion. 1273 55

The roles of cardiomyocyte sarcolemmal ATP-sensitive K(+) (K(ATP)) and mitochondrial K(ATP) channels in the cardioprotection and antiarrhythmic activity induced by K(ATP) channel openers remain obscure, though the mitochondrial K(ATP) channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers (nicorandil and cromakalim), a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal K(ATP) channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n=80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30min. In Group II (n=184), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. Both in Groups I and II, early intravenous infusion of nicorandil (100 micro g/kg bolus+10 micro g/kg/min), cromakalim (0.2 micro g/kg/min), HMR 1883 (3mg/kg)/nicorandil and HMR 1883 (3mg/kg)/cromakalim just prior to and during ischemia increased survival rate (75%, 67%, 86% and 75% versus 60% in the control subgroup in Group I; 75%, 75%, 75% and 67% versus 50% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or cromakalim at the onset and during reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and cromakalim were abolished by pretreating the rabbits with 5-HD (5mg/kg, i.v. bolus), a selective mitochondrial K(ATP) channel blocker but not by HMR 1883 (3mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and cromakalim.We, therefore, conclude that intervention by intravenous administration of nicorandil and cromakalim (through the selective activation of mitochondrial K(ATP) channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. The mitochondrial K(ATP) channel may be a potential site of cardioprotection and antiarrhythmic activity.
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PMID:Mitochondrial K ATP channel activation is important in the antiarrhythmic and cardioprotective effects of non-hypotensive doses of nicorandil and cromakalim during ischemia/reperfusion: a study in an intact anesthetized rabbit model. 1274 97

Recent evidence suggests that the mitochondrial K(ATP) channels may be involved as a subcellular mediator in cardioprotection afforded by ischemic and pharmacological preconditioning by K(ATP) activators. The present study investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers, nicorandil (NIC) and pinacidil (PIN), and specific blockers of mitochondrial (5-hydroxydecanoate) and sarcolemmal (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methyl-thiourea, HMR 1883) K(ATP) channels prior to and during coronary occlusion and post-ischemic reperfusion on survival rate, ischemia- and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized rabbits. In Group I, myocardial ischemia-induced arrhythmias were provoked by tightening a ligature over the left main coronary artery for 30 min. In Group II, arrhythmias were induced by reperfusion following a 20 min ligation of the same artery. Both in Group I and Group II, early iv administration of NIC (0.47 mg/kg), PIN (0.1 mg/kg), HMR 1883 (3 mg/kg)/NIC and HMR 1883/PIN just prior to and during ischemia increased survival rate (75%, 86%, 75% and 75%, respectively, vs. 55% in the control in Group I; 75%, 75%, 75% and 67%, respectively, vs. 50% in the control in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late iv administration of NIC or PIN just prior to reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects were abolished by pretreating rabbits with 5-hydroxy-decanoate (5 mg/kg, iv bolus). In the present study, higher levels of malondialdehyde and lower levels of reduced glutathione and superoxide dismutase in necrotic zone of myocardium in all subgroups in Group II suggest little anti-free radical property of NIC and PIN. Therefore, it may be assumed that mitochondrial K(ATP) channel opening leads to mitochondrial generation and release of ROS providing for IPC and antiarrhythmic activity. The mitochondrial rather than sarcolemmal K(ATP) channel may represent a potential site of cardioprotection and antiarrhythmic activity.
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PMID:Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model. 1470 74

In the present study, a novel sulfonylthiourea, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), was investigated using in vitro and in vivo systems. HMR 1402 inhibited rilmakalim-induced currents in rat and guinea pig myocytes (IC(50) = 60 and 509 nM, respectively). Hypoxia-induced shortening of action potential duration at 90% repolarization was also significantly attenuated by HMR 1402 (68.1 +/- 3.9% of control at 0.3 microM). In contrast, HMR 1402 had a smaller effect on pancreatic beta-cells (rat insuloma cells, RINm5F) hyperpolarized with 100 microM diazoxide (IC(50) = 3.9 microM, compared with glibenclamide IC(50) = 9 nM). In a similar manner, hypoxia induced increases in coronary flow in isolated guinea pig hearts were only slightly reduced by HMR 1402. These data strongly suggest that HMR 1402 has pharmacological selectivity for cardiac myocytes and, therefore, may protect against ischemically induced ventricular fibrillation (VF) without the untoward effects of nonselective compounds. To test this hypothesis, VF was induced in 8 dogs with healed myocardial infarctions by a 2-min coronary occlusion during the last minute of exercise. On a subsequent day, the exercise plus ischemia test was repeated after HMR 1402 (3.0 mg/kg i.v., n = 4, infusion 4 microg/kg/min for 1 h before exercise, n = 4). This drug significantly reduced the incidence of VF protecting seven of eight animals (p = 0.0007) without altering plasma insulin, blood glucose, or the increases in mean coronary blood flow induced by either exercise or 15-s coronary occlusions. Thus, the ATP-sensitive potassium channel antagonist HMR 1402 can prevent ischemically induced VF without altering coronary blood flow or blood glucose.
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PMID:Effects of a novel cardioselective ATP-sensitive potassium channel antagonist, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), on susceptibility to ventricular fibrillation induced by myocardial ischemia: in vitro and in vivo studies. 1472 26

During heart ischemia, ATP-sensitive potassium channels in the sarcolemmal membrane (sarcK(ATP)) open and cause shortening of the action potential duration. This creates heterogeneity of repolarization, being responsible for the development of re-entry arrhythmias and sudden cardiac death. Therefore, the aim is to develop selective blockers of the cardiac sarcK(ATP) channel. In the present study we established an in vitro model and classified 5 K(ATP) channel inhibitors with respect to their potency and selectivity between cardiomyocytes and the coronary vasculature and compared the results with inhibition of Kir6.2/SUR2A channels expressed in HEK293 cells, recorded with the Rb(+)-efflux methods. We used Langendorff-perfused guinea pig hearts, where low-flow ischemia plus hypoxia was performed by reducing the coronary flow (CF) to 1.2 ml/min and by gassing the perfusion solution with N(2) instead of O(2). Throughout the experiment, the monophasic action potential duration at 90% repolarization (MAPD(90)) was recorded. In separate experiments, high-flow hypoxia was produced by oxygen reduction in the perfusate from 95% to 20%, which caused an increase in the coronary flow. Under normoxic conditions, the substances glibenclamide, repaglinide, meglitinide, HMR 1402 and HMR 1098 (1 microM each) reduced the CF by 34%, 38%, 19%, 12% and 5%, respectively. The hypoxia-induced increase in CF was inhibited by the compounds half-maximally at 25 nM, approximately 200 nM, 600 nM, approximately 9 microM and >100 microM, respectively. In control experiments after 5 min low-flow ischemia plus hypoxia, the MAPD(90) shortened from 121+/-2 to 99+/-2 ms ( n=29). This shortening was half-maximally inhibited by the substances at concentrations of 95 nM, 74 nM, 400 nM, 110 nM and 550 nM, respectively. In HEK293 cells the Rb(+)-efflux through KIR6.2/SUR2A channels was inhibited by the compounds with IC(50) values of 21 nM, 67 nM, 205 nM, 60 nM and 181 nM, respectively. In summary, the present data demonstrate that the sulfonylurea glibenclamide, and the carbamoylbenzoic acid derivatives repaglinide and meglitinide are unselective blockers of K(ATP) channels in cardiac cells and in the cardiac vascular system, whereas the sulfonylthioureas HMR 1402, and especially HMR 1098 selectively blocked the cardiac sarcK(ATP) channel. Blockade of Kir6.2/SUR2A channels in HEK293 cells occurred with comparable efficacy as in the cardiac tissue, indicating that the expression system is suited for screening for novel inhibitors.
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PMID:Inhibitors of ATP-sensitive potassium channels in guinea pig isolated ischemic hearts. 1502 53

Mitochondrial permeability transition (mPT) is a crucial event in the progression to cell death in the setting of ischemia-reperfusion. We have used a model system in which mPT can be reliably and reproducibly induced to test the hypothesis that the profound protection associated with the phenomenon of myocardial preconditioning is mediated by suppression of the mPT. Adult rat myocytes were loaded with the fluorescent probe tetramethylrhodamine methyl ester, which generates oxidative stress on laser illumination, thus inducing the mPT (indicated by collapse of the mitochondrial membrane potential) and ATP depletion, seen as rigor contracture. The known inhibitors of the mPT, cyclosporin A (0.2 microM) and N-methyl-4-valine-cyclosporin A (0.4 microM), increased the time taken to induce the mPT by 1.8- and 2.9-fold, respectively, compared with control (P < 0.001) and rigor contracture by 1.5-fold compared with control (P < 0.001). Hypoxic preconditioning (HP) and pharmacological preconditioning, using diazoxide (30 microM) or nicorandil (100 microM), also increased the time taken to induce the mPT by 2.0-, 2.1-, and 1.5-fold, respectively (P < 0.001), and rigor contracture by 1.9-, 1.7-, and 1.5-fold, respectively, compared with control (P < 0.001). Effects of HP, diazoxide, and nicorandil were abolished in the presence of mitochondrial ATP-sensitive K(+) (K(ATP)) channel blockers glibenclamide (10 microM) and 5-hydroxydecanoate (100 microM) but were maintained in the presence of the sarcolemmal K(ATP) channel blocker HMR-1098 (10 microM). In conclusion, preconditioning protects the myocardium by reducing the probability of the mPT, which normally occurs during ischemia-reperfusion in response to oxidative stress.
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PMID:Preconditioning protects by inhibiting the mitochondrial permeability transition. 1507 53


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