Abstract 1554: PX-18 - A Novel Inhibitor of Type IIA Secretory Phospholipase A 2 Induces Pre and Post-Conditioning against Myocardial Infarction in Rabbit: Role of Mitochondrial K ATP Channels.

Abstract

Background: The low-molecular-weight, calcium-dependent type IIA secretory phospholipase A 2 (sPLA 2 ) has been implicated in irreversible cell damage following ischemia-reperfusion (I/R) injury. We examined the protective effect of PX-18, a novel sPLA 2 inhibitor, during I/R in the heart. Since mitochondrial K ATP (mitoK ATP ) channel opening is an essential component of ischemic tolerance induced by preconditioning in hearts, we also interrogated the role of these channels in PX-18-induced protection. Methods and Results: Rabbits were treated with PX-18 (60 mg/kg ip) 30 min prior to 30 min of regional ischemia and 3 hrs of reperfusion. MitoK ATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg iv) was given 10 min before I/R. Infarct size (IS) was measured by computer morphometry of tetrazolium stained sections. IS (mean ± SE) was reduced in rabbits treated with PX-18 as compared to vehicle or non-treated controls (43% reduction)[Fig.1 ]. 5-HD blocked the protection of PX-18 as shown by an increase in IS. 5-HD alone had no effect on IS. Risk areas were not different among groups (not shown). Furthermore, PX-18 administration as an iv bolus (30 mg/kg) further reduced IS, both when given post-ischemia (55% reduction), and, importantly, when given 1 hr after reperfusion (61% reduction) [Fig. 1 ]. PX-18 had no significant effect on hemodynamics. Conclusion: These data suggest that PX-18 induces pharmacological preconditioning in the heart which is mediated by opening of mitoK ATP channels. Also, the drug was cardioprotective when administered after ischemia or 1 hr after reperfusion. We conclude that inhibition of sPLA2 is a powerful strategy to induce protection against I/R injury.