Abstract 4342390: Myocardial Protection by Adenosine Triphosphate-Sensitive Potassium Channel Opener Diazoxide Involves Sulfonylurea Receptor (SUR) 2 Subunit

Abstract

Objective: Pharmacologic opening of the adenosine triphosphate-sensitive potassium (K ATP ) channel mimics ischemic preconditioning and is cardioprotective. The components of a definitive mitochondrial K ATP channel have not been identified, although several candidates have been proposed. We have investigated various subunits (Kir1.1, SUR1, Kir6.1, Kir6.2) as candidates, but none has been implicated. To complete the assessment of known K ATP channel components, we hypothesized that SUR2 would be implicated in diazoxide (DZX) cardioprotection in a model of prolonged global myocardial ischemia. Methods: Mice lacking SUR2 (KO) and wild-type (WT) litter mates were randomly assigned to 90 min global ischemia in a Langendorff model following hypothermic hyperkalemic cardioplegia with or without DZX (100 µM/L) (N=9-14 per group). Left ventricular developed pressure (LVDP), end diastolic pressure (EDP), and coronary flow were compared before and after ischemia. Pressures were measured over a series of identical intracavitary balloon volumes. Percent change in EDP and LVDP from baseline by balloon volume and mouse type groups were examined using ANOVA with Huynh-Feldt correction. Results provided the main effect (ME) of balloon volume (regardless of group), ME of mouse type groups, and interaction of balloon volume and group. Results: Baseline LVDP was lower in SUR2 KO mice compared to WT ( P < 0.001). Baseline EDP was not different between SUR2 KO and WT mice ( P = 0.766). WT mice had decreased LVDP (relative to baseline) after global ischemia that was prevented by DZX; however, SUR2 KO mice had decreased LVDP (relative to baseline) that was not responsive to DZX (Fig A). WT mice had increased EDP (relative to baseline) after global ischemia that was prevented by DZX; however, SUR2 KO mice had increased EDP that was not responsive to DZX (Fig B). Coronary flow was not different between groups, confirming the consistent perfusion in all experiments. Conclusions: This study in a global ischemia isolated heart model suggests that SUR2 is involved in cardioprotection by the K ATP channel opener DZX. This model mimics the clinical situation of global arrest in cardiac surgery. SUR2 is the first K ATP channel subunit suggested to be involved in DZX cardioprotection. Identification of subunits of a cardioprotective K ATP channel may allow targeted pharmacologic therapy to reduce myocardial stunning following global ischemia during cardiac surgery.