Preconditioning-induced cardioprotection and release of the second messenger inositol (1,4,5)-trisphosphate are both abolished by neomycin in rabbit heart.
The mechanisms responsible for infarct size reduction with preconditioning remain controversial. Our aim was to determine whether release of the second messenger inositol (1,4,5)-triphosphate (Ins(1,4,5)P3) during the preconditioning stimulus may play a role. To test this concept, Langendorff-perfused rabbit hearts underwent sham perfusion, 5 min of coronary artery occlusion (CO), or 5 min of CO + infusion of neomycin, an agent which inhibits formation of Ins(1,4,5)P3. Direct quantitation (by competitive binding assay) revealed a 2-fold increase in Ins(1,4,5)P3 content with brief ischemia vs shams (0.69 +/- 0.14 vs 0.34 +/- 0.05 pmol/mg tissue; p < .05) that was blocked by neomycin (0.15 +/- 0.04 pmol/mg). Infarct size (by tetrazolium staining) was assessed in additional hearts that underwent 30 min of sustained CO and 2 h of reperfusion. As expected, two 5-min episodes of preconditioning ischemia reduced infarct size versus controls (30 +/- 6% versus 63 +/- 3% of the myocardium at risk; p < .01). In contrast, infarct size was comparable (54-56% of the risk region) in neomycin-treated control and preconditioned hearts. These results demonstrate that myocardial Ins(1,4,5)P3 content is increased in response to brief preconditioning ischemia and are consistent with the concept that Ins(1,4,5)P3 may be a potential mediator of infarct size reduction with preconditioning in isolated rabbit heart.
Bauer
B
B
Heart Institute/Research, Good Samaritan Hospital, Los Angeles, CA 90017-2395, USA.
Simkhovich
B Z
BZ
Kloner
R A
RA
Przyklenk
K
K
D000818:Animals; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D009355:Neomycin / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D015290:Second Messenger Systems / Q000187:drug effects* / Q000502:physiology
D011500:Protein Synthesis Inhibitors; D015544:Inositol 1,4,5-Trisphosphate; D009355:Neomycin