Cardioprotection by cariporide after prolonged hypothermic storage of the isolated working rat heart.
BACKGROUND
Inhibition of the sodium-hydrogen (Na(+)-H(+)) exchanger decreases the extent of ischemia-reperfusion injury in the myocardium. Inhibition may also improve preservation of hearts stored for transplantation. Our aim was to characterize the dose response and to determine optimal timing for administering cariporide, an Na(+)-H(+) exchange inhibitor, during prolonged hypothermic storage.


METHODS
We used the rat isolated working-heart model to measure cardiac function. To determine the optimal dose of cariporide, hearts received either no treatment (control) or incremental doses of cariporide (1, 3.2, 10, or 30 micromol/liter) before storage and during reperfusion. Hearts were arrested with and stored in an extracellular-based cardioplegic solution at 2 to 3 degrees C for 6 hours. To determine optimal timing, we arrested a group of hearts with and stored them in a cariporide-supplemented (10 micromol/liter) cardioplegic solution but did not pre-treat them with cariporide. Finally, we treated a separate group of hearts with 10 micromol/liter cariporide before, during, and after storage.


RESULTS
Recovery of cardiac function in control hearts was poor. The cardioprotective effect of cariporide was dose dependent, with maximal protection observed at a concentration of 10 micromol/liter. Storing hearts in a cariporide-supplemented cardioplegic solution did not result in better recovery of cardiac function compared with cariporide given before storage and during reperfusion. Moreover, recovery of cardiac function was significantly worse in hearts that had not been pre-treated with cariporide.


CONCLUSIONS
Sodium-hydrogen-exchange inhibition with cariporide significantly protects the hypothermic ischemic rat heart, increasing cardiac function after reperfusion. The timing of cariporide administration is an important determinant of this cardioprotection.
Cropper
Jonathan Rhys David
JR
Victor Chang Cardiac Research Institute, St Vincent's Hopsital, Darlinghurst, New South Wales, Australia.
Hicks
Mark
M
Ryan
Jonathon Bruce
JB
Macdonald
Peter Simon
PS
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006146:Guanidines / Q000008:administration & dosage*; D007036:Hypothermia, Induced / Q000009:adverse effects*; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013450:Sulfones / Q000008:administration & dosage*; D013997:Time Factors
D002316:Cardiotonic Agents; D006146:Guanidines; D013450:Sulfones; C093373:cariporide