Pretreatment with d-myo-Inositol Trisphosphate Reduces Infarct Size in Rabbit Hearts: Role of Inositol Trisphosphate Receptors and Gap Junctions in Triggering Protection

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Abstract
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 IP3 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-IP3 + 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.

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