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 secon d messenger inositol (1,4,5)-trisphosphate (Ins(1,4,5)P-3) during the preco nditioning stimulus may play a role. To test this concept, Langendorff-perf used rabbit hearts underwent sham perfusion, 5 min of coronary artery occlu sion (CO), or 5 min of CO + infusion of neomycin, an agent which inhibits f ormation of Ins(1,4,5)P-3. Direct quantitation (by competitive binding assa y) revealed a 2-fold increase in Ins(1,4,5)P-3 content with brief ischemia vs shams (0.69 +/- 0.14 vs 0.34 +/- 0.05 pmol/mg tissue; p <.05) that was b locked by neomycin (0.15 +/- 0.04 pmol/mg). Infarct size (by tetrazolium st aining) was assessed in additional hearts that underwent 30 min of sustaine d CO and 2 h of reperfusion. As expected, two 5-min episodes of preconditio ning ischemia reduced infarct size versus controls (30 +/- 6% versus 63 +/- 3 % of the myocardium at risk; p <.01). In contrast, infarct size was comp arable (54 - 56 % of the risk region) in neomycin-treated control and preco nditioned hearts. These results demonstrate that myocardial Ins(1,4,5)P-3 c ontent is increased in response to brief preconditioning ischemia and are c onsistent with the concept that Ins(1,4,5)P-3 may be a potential mediator o f infarct size reduction with preconditioning in isolated rabbit heart.