title: Pretreatment with D-myo-inositol trisphosphate reduces infarct size in rabbit hearts: role of inositol trisphosphate receptors and gap junctions in triggering protection.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, 01655, USA. karin.przyklenk@umassmed.edu
authors.forename: Karin
authors.initials: K
authors.lastname: Przyklenk
authors.forename: Michelle
authors.initials: M
authors.lastname: Maynard
authors.forename: Chad E
authors.initials: CE
authors.lastname: Darling
authors.forename: Peter
authors.initials: P
authors.lastname: Whittaker
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology / Q000627:therapeutic use*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009203:Myocardial Infarction / Q000188:drug therapy*; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate