Enhanced cardioprotection of the rat heart during hypothermic storage with combined Na+ - H+ exchange inhibition and ATP-dependent potassium channel activation.
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 micromol/liter) or BMS-180448 (10 micromol/liter) or with the Na(+)-H(+) exchanger inhibitor cariporide (10 micromol/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 degrees 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.
Victor Chang Cardiac Research Institute, University of New South Wales, Sydney, Australia.
Jonathan Rhys David
JR
Cropper
Mark
M
Hicks
Jonathon Bruce
JB
Ryan
Peter Simon
PS
Macdonald
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation; D007036:Hypothermia, Induced; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D002316:Cardiotonic Agents; D006146:Guanidines; D013450:Sulfones; D014665:Vasodilator Agents; C093373:cariporide; C084684:BMS 180448; D000254:Sodium-Potassium-Exchanging ATPase; D003981:Diazoxide