Enhanced cardioprotection of the rat heart during hypothermic storage with combined Na +-H + exchange inhibition and ATP-dependent potassium channel activation

Abstract

Background We investigated the ability of mitochondrial adenosine triphosphate–dependent potassium-channel activation to augment the protection of Na +-H + exchanger inhibition in isolated working rat hearts after 6 hours of hypothermic storage in an extracellular-based cardioplegic solution. Methods We treated hearts with the potassium-channel openers diazoxide (100 μmol/liter) or BMS-180448 (10 μmol/liter) or with the Na +-H + exchanger inhibitor cariporide (10 μmol/liter). Cariporide also was administered in combination with either diazoxide or BMS-180448 in 2 other treatment groups. All hearts were arrested and stored at 2 to 3°C. After storage, we reperfused hearts for 10 minutes before performing work for a further 15 minutes, and then we measured and assessed cardiac function using a 2-way analysis of variance model. Results Neither diazoxide nor BMS-180448 significantly improved recovery of cardiac output. Cariporide therapy significantly improved cardiac output compared with control. However, we obtained the greatest recovery of cardiac output when we combined cariporide with either diazoxide or BMS-180448. Conclusions Cariporide is more cardioprotective than the potassium-channel openers diazoxide and BMS-180448 after prolonged hypothermic storage. Co-administration of diazoxide or BMS-180448 with cariporide results in additive cardioprotection, with significantly improved cardiac function when compared with either treatment given alone. Such a combination could be used to improve the functional recovery of hearts stored for cardiac transplantation.