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dc.contributor.authorPrzyklenk, Karin
dc.contributor.authorMaynard, Michelle
dc.contributor.authorDarling, Chad E.
dc.contributor.authorWhittaker, Peter
dc.date2022-08-11T08:09:33.000
dc.date.accessioned2022-08-23T16:35:41Z
dc.date.available2022-08-23T16:35:41Z
dc.date.issued2005-05-28
dc.date.submitted2009-03-26
dc.identifier.citationJ Pharmacol Exp Ther. 2005 Sep;314(3):1386-92. Epub 2005 May 26. <a href="http://dx.doi.org/10.1124/jpet.105.087742">Link to article on publisher's site</a>
dc.identifier.issn0022-3565 (Print)
dc.identifier.doi10.1124/jpet.105.087742
dc.identifier.pmid15919762
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38614
dc.description.abstractPretreatment with D-myo-inositol-1,4,5-trisphosphate hexasodium (D-myo-IP(3)), the sodium salt of the second messenger inositol 1,4,5-trisphosphate (IP(3)), is cardioprotective and triggers a reduction of infarct size comparable in magnitude to that obtained with ischemic preconditioning. However, this observation is enigmatic; whereas IP(3) signaling is conventionally initiated by receptor binding, IP(3) receptors are typically considered to be intracellular, and D-myo-IP(3) is membrane-impermeable. We propose that this paradox is explained by the presence of poorly characterized external IP(3) receptors and hypothesize that: 1) infarct size reduction with D-myo-IP(3) is receptor-mediated; and 2) communication via gap junctions and/or hemichannels is required to initiate this protection. To investigate the role of receptor binding, isolated buffer-perfused rabbit hearts underwent 30 min of coronary occlusion (CO) and 2 h of reflow. Prior to CO, hearts received no treatment (controls), D-myo-IP(3), L-myo-IP(3) (enantiomer not recognized by the IP(3) receptor), D-myo-IP(3) + the IP(3) receptor inhibitor xestospongin C (XeC), or XeC alone. Infarct size, assessed by tetrazolium staining, was reduced with D-myo-IP(3) treatment, whereas hearts that received L-myo-IP(3) or D-myo-IP(3) + XeC showed no protection. To evaluate the contribution of gap junctions/hemichannels, additional control and D-myo-IP(3)-treated cohorts received a 5-min infusion of heptanol or Gap 27, two structurally distinct gap junction inhibitors, administered at doses confirmed to attenuate intercellular transmission of a gap junction-permeable fluorescent dye. There was no infarct-sparing effect of D-myo-IP(3) in inhibitor-treated hearts. These data support the concepts that infarct size reduction with D-myo-IP(3) is triggered by receptor binding and that communication via gap junctions/hemichannels is involved in initiating this protection.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=15919762&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1124/jpet.105.087742
dc.subjectAnimals
dc.subjectCalcium Channels
dc.subjectGap Junctions
dc.subjectInositol 1,4,5-Trisphosphate
dc.subjectInositol 1,4,5-Trisphosphate Receptors
dc.subjectMyocardial Infarction
dc.subjectRabbits
dc.subjectReceptors, Cytoplasmic and Nuclear
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titlePretreatment with D-myo-inositol trisphosphate reduces infarct size in rabbit hearts: role of inositol trisphosphate receptors and gap junctions in triggering protection
dc.typeJournal Article
dc.source.journaltitleThe Journal of pharmacology and experimental therapeutics
dc.source.volume314
dc.source.issue3
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1477
dc.identifier.contextkey798452
html.description.abstract<p>Pretreatment with D-myo-inositol-1,4,5-trisphosphate hexasodium (D-myo-IP(3)), the sodium salt of the second messenger inositol 1,4,5-trisphosphate (IP(3)), is cardioprotective and triggers a reduction of infarct size comparable in magnitude to that obtained with ischemic preconditioning. However, this observation is enigmatic; whereas IP(3) signaling is conventionally initiated by receptor binding, IP(3) receptors are typically considered to be intracellular, and D-myo-IP(3) is membrane-impermeable. We propose that this paradox is explained by the presence of poorly characterized external IP(3) receptors and hypothesize that: 1) infarct size reduction with D-myo-IP(3) is receptor-mediated; and 2) communication via gap junctions and/or hemichannels is required to initiate this protection. To investigate the role of receptor binding, isolated buffer-perfused rabbit hearts underwent 30 min of coronary occlusion (CO) and 2 h of reflow. Prior to CO, hearts received no treatment (controls), D-myo-IP(3), L-myo-IP(3) (enantiomer not recognized by the IP(3) receptor), D-myo-IP(3) + the IP(3) receptor inhibitor xestospongin C (XeC), or XeC alone. Infarct size, assessed by tetrazolium staining, was reduced with D-myo-IP(3) treatment, whereas hearts that received L-myo-IP(3) or D-myo-IP(3) + XeC showed no protection. To evaluate the contribution of gap junctions/hemichannels, additional control and D-myo-IP(3)-treated cohorts received a 5-min infusion of heptanol or Gap 27, two structurally distinct gap junction inhibitors, administered at doses confirmed to attenuate intercellular transmission of a gap junction-permeable fluorescent dye. There was no infarct-sparing effect of D-myo-IP(3) in inhibitor-treated hearts. These data support the concepts that infarct size reduction with D-myo-IP(3) is triggered by receptor binding and that communication via gap junctions/hemichannels is involved in initiating this protection.</p>
dc.identifier.submissionpathoapubs/1477
dc.contributor.departmentDepartment of Emergency Medicine
dc.source.pages1386-92


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