Abstract 15530: Renal Outer Medullary Potassium (Kir 1.1) is not the Kir Subunit of a Cardioprotective, Diazoxide - Mediated Mitochondrial Adenosine Triphosphate - Sensitive Potassium Channel

Abstract

Objective: The adenosine triphosphate-sensitive potassium (K ATP ) channel opener diazoxide (DZX) mimics ischemic preconditioning and is cardioprotective. The molecular mechanism of action is unknown, although several mitochondrial candidate protein targets have been proposed. We suggested that cardioprotection occurs at a non-sarcolemmal channel, requires the inhibition of succinate dehydrogenase, and involves K ATP channel subunit SUR1. The renal outer medullary potassium channel (ROMK, or Kir1.1) subunit was proposed as the Kir subunit of a mitochondrial (m)K ATP channel. We tested the hypothesis that genetic deletion of ROMK will result in loss of DZX cardioprotection in a model of prolonged ischemia with cardioplegia. Methods: Mice lacking ROMK in cardiac myocytes (cKO) and wild-type (WT) litter mates were randomly assigned to 90 min. global ischemia in a Langendorff model following hypothermic hyperkalemic cardioplegia (CPG) or CPG + DZX (100 μM/L) (N=6-9 per group). Left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and coronary flow were compared before and after global ischemia. Data acquisition and interpretation were blinded to group. Results: Similar to previous results, prolonged global ischemia was associated with a reduction in LVDP and an increase in EDP with CPG that was prevented by DZX in WT. Unexpectedly, ROMK (cKO) mice were equally responsive to DZX (Figure), indicating that DZX protection is not mediated by ROMK channels. Conclusions: Genetic deletion of ROMK in cardiac myocytes does not negate cardioprotection provided by DZX, indicating ROMK is not a subunit of a cardioprotective mK ATP channel. Alternate proposed DZX-sensitive target channels or mechanisms of action remain to be tested. Identification of the specific subunits of a mK ATP channel would allow for targeted pharmacologic therapy to reduce myocardial stunning following prolonged ischemia, similar to that seen following cardiac surgery.