Abstract 427: Inhibition of Myocardial Romk Channels Blocks Ischemic Preconditioning Induced Cardio-protection

Background: Prior evidence has shown that the renal outer medullary potassium channel (Kir 1.1 or ROMK) may be the pore forming subunit of the mitochondrial KATP channel (mitoKATP). However, it is unknown if ROMK inhibition affects myocardial function after ischemia reperfusion injury or cardio-protection from ischemic preconditioning. Methods: C57/BL6J mice were subjected to ex vivo ischemia (45 min) and then reperfusion (60 min) with or without ischemic preconditioning (3 cycles of 3 min). Mice were treated throughout the protocol with either 5 μM of compound A, a potent ROMK inhibitor, or vehicle, in a modified Krebs Henseliet buffer. Results: WT mice hearts subjected to ischemia reperfusion injury and perfused with 5 μM compound A recovered 73% of baseline left ventricular developed pressure (LVDP) while mouse hearts perfused with vehicle recovered 50% of baseline LVDP (P=0.07, N=3). Infarct size was not significantly different between hearts perfused with 5 μM compound A or vehicle (32% ± 7% vs. 46% ± 10%, P =0.18, N=3). In vehicle perfused mice, IPC significantly improved % recovery of LVDP (IPC 87% ± 9% vs. no IPC 50% ± 7%, P =0.014, N=3) and infarct size (IPC 22% ± 4% vs no IPC 46% ± 11%, P =0.02, N=3). However, IPC did not improve % recovery of LVDP (IPC 69% ± 6% vs no IPC 73% ± 4%, P =0.33, N=3) or infarct size (IPC 46% ± 14% vs no IPC 32% ± 7%, P =0.22, N=3) in mouse hearts perfused with compound A. Conclusions: Myocardial ROMK inhibition does not increase IR injury in an ex vivo mouse preparation, but does block cardio-protection from IPC further supporting ROMK as the potential pore forming channel of mitoKATP.