Superior diastolic function with K ATP channel opener diazoxide in a novel mouse Langendorff model

Abstract

Prolongation of global ischemia demonstrated added benefit when DZX was added to traditional hyperkalemic CPG. This model will allow the investigation of DZX mechanism of cardioprotection following manipulation of targeted K channel components. This model will also allow translation to prolonged ischemic episodes associated with cardiac surgery.

Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive

“…5 Pharmacologic opening of K ATP channels mimics ischemic preconditioning in multiple animal models. [6][7][8][9][10][11] DZX was found to preserve diastolic function in a murine model of prolonged global ischemia and preserves systolic and diastolic function in a large animal model of prolonged cardioplegic arrest. 11,12 The molecular mechanism of this cardioprotection is unknown, but we have suggested that it involves a mitochondrial location 13 and requires the inhibition of succinate dehydrogenase (SDH) 14 and the K ATP channel sulfonylurea subunit 1 (SUR1).…”

“…[6][7][8][9][10][11] DZX was found to preserve diastolic function in a murine model of prolonged global ischemia and preserves systolic and diastolic function in a large animal model of prolonged cardioplegic arrest. 11,12 The molecular mechanism of this cardioprotection is unknown, but we have suggested that it involves a mitochondrial location 13 and requires the inhibition of succinate dehydrogenase (SDH) 14 and the K ATP channel sulfonylurea subunit 1 (SUR1). 15 Clarification of DZX's cardioprotective mechanism of action is vital to its future use in clinical trials as a component of hyperkalemic CPG.…”

“…Mice (either sex; C57BL/6J) were anesthetized and underwent rapid cardiectomy as described previously (Video 2). 11 The heart was submersed in ice-cold Krebs-Henseleit buffer for each). The MitoSNO dose was chosen based on the dose response in isolated myocytes.…”

“…Coronary flow rates were measured every 5 minutes by an inline N-series flow probe and a T206 flow meter (Transonic Systems, Ithaca, NY) and compared as described previously. 11 Statistical analysis. A linear mixed model was used to obtain correct standard errors for estimates of treatment effects in the presence of subjectlevel correlation among measurements of LVDP or EDP (Online Data Supplement).…”

“…The LV balloon volume was then returned to the initial volume, and the heart was arrested for 90 minutes using test solution.Randomly assigned test solutions included hyperkalemic CPG (Plegisol) (110 mmol/L NaCl, 10 mmol/L NaHCO 3 , 16 mmol/L KCl, 32 mmol/L Mg, and 2.4 mmol/L CaCl 2 , titrated to pH 7.8 with 8.4% NaHCO 3 solution) or CPG þ DZX 100 mmol/L (Sigma-Aldrich). The DZX dose was chosen based on previous experiments 11. After 90 minutes of global ischemia, hearts were assigned at random to receive MitoSNO 1 mmol/L (n ¼ 8 with CPG, n ¼ 10 with CPG þ DZX) or KHB (n ¼ 8…”