TY - JOUR
T1 - Pretreatment with D-myo-inositol trisphosphate reduces infarct size in rabbit hearts
T2 - Role of inositol trisphosphate receptors and gap junctions in triggering protection
AU - Przyklenk, Karin
AU - Maynard, Michelle
AU - Darling, Chad E.
AU - Whittaker, Peter
PY - 2005/9
Y1 - 2005/9
N2 - Pretreatment with D-myo-inositol-1,4,5-trisphosphate hexasodium (D-myo-IP3), the sodium salt of the second messenger inositol 1,4,5-trisphosphate (IP3), is cardioprotective and triggers a reduction of infarct size comparable in magnitude to that obtained with ischemic preconditioning. However, this observation is enigmatic; whereas IP3 signaling is conventionally initiated by receptor binding, IP3 receptors are typically considered to be intracellular, and D-myo-IP3 is membrane-impermeable. We propose that this paradox is explained by the presence of poorly characterized external IP3 receptors and hypothesize that: 1) infarct size reduction with D-myo-IP3 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-IP3, L-myo-IP3 (enantiomer not recognized by the IP3 receptor), D-myo-IP3 + the IP 3 receptor inhibitor xestospongin C (XeC), or XeC alone. Infarct size, assessed by tetrazolium staining, was reduced with D-myo-IP3 treatment, whereas hearts that received L-myo-IP3 or D-myo-IP 3 + XeC showed no protection. To evaluate the contribution of gap junctions/hemichannels, additional control and D-myo-IP3-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-IP3 in inhibitor-treated hearts. These data support the concepts that infarct size reduction with D-myo-IP3 is triggered by receptor binding and that communication via gap junctions/hemichannels is involved in initiating this protection.
AB - Pretreatment with D-myo-inositol-1,4,5-trisphosphate hexasodium (D-myo-IP3), the sodium salt of the second messenger inositol 1,4,5-trisphosphate (IP3), is cardioprotective and triggers a reduction of infarct size comparable in magnitude to that obtained with ischemic preconditioning. However, this observation is enigmatic; whereas IP3 signaling is conventionally initiated by receptor binding, IP3 receptors are typically considered to be intracellular, and D-myo-IP3 is membrane-impermeable. We propose that this paradox is explained by the presence of poorly characterized external IP3 receptors and hypothesize that: 1) infarct size reduction with D-myo-IP3 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-IP3, L-myo-IP3 (enantiomer not recognized by the IP3 receptor), D-myo-IP3 + the IP 3 receptor inhibitor xestospongin C (XeC), or XeC alone. Infarct size, assessed by tetrazolium staining, was reduced with D-myo-IP3 treatment, whereas hearts that received L-myo-IP3 or D-myo-IP 3 + XeC showed no protection. To evaluate the contribution of gap junctions/hemichannels, additional control and D-myo-IP3-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-IP3 in inhibitor-treated hearts. These data support the concepts that infarct size reduction with D-myo-IP3 is triggered by receptor binding and that communication via gap junctions/hemichannels is involved in initiating this protection.
UR - http://www.scopus.com/inward/record.url?scp=23944457139&partnerID=8YFLogxK
U2 - 10.1124/jpet.105.087742
DO - 10.1124/jpet.105.087742
M3 - Article
C2 - 15919762
AN - SCOPUS:23944457139
VL - 314
SP - 1386
EP - 1392
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -