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CARDIOVASCULAR

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

Departments of Emergency Medicine (K.P., M.M., C.E.D., P.W.) and Anesthesiology (K.P., P.W.), University of Massachusetts Medical School, Worcester Massachusetts

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.

Address correspondence to: Dr. Karin Przyklenk, Department of Emergency Medicine, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655. E-mail: karin.przyklenk{at}umassmed.edu

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