Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury.
BACKGROUND
In clinical trials, perioperative intravenous Na(+)/H(+) exchange isoform-1 (NHE1) inhibitors were only moderately effective in high-risk patients undergoing surgical reperfusion (GUARDIAN trial). However, effective myocardial concentrations of NHE1 inhibitor may not have been achieved by parenteral administration alone. We tested the hypothesis that increasing doses of NHE1 inhibitor EMD 87580 ((2-methyl-4,5-di-(methylsulfonyl)-benzoyl)-guanidine) delivered in blood cardioplegia (BCP) and by parenteral route at reperfusion reduce myocardial injury after surgical reperfusion of evolving infarction.


METHODS
Twenty-six anesthetized dogs underwent 75 minutes of left anterior descending coronary artery occlusion, followed by cardiopulmonary bypass and 60 minutes of arrest with multidose 10 degrees C BCP. In the control group (n = 8), BCP was not supplemented. In the three EMD-BCP groups, BCP was supplemented with 10 micromol/L EMD 87580 (EMD-10, n = 5), 20 micromol/L EMD 87580 (EMD-20, n = 5), or 20 micromol/L EMD 87580 combined with an immediate reperfusion bolus (5 mg/kg intravenously) (EMD-20R, n = 8). The left anterior descending coronary artery occlusion was released just before the second infusion of BCP. Reperfusion continued for 120 minutes after discontinuation of cardiopulmonary bypass.


RESULTS
Postischemic systolic and diastolic function in the area at risk was dyskinetic in all groups. Infarct size (percentage of area at risk) was not significantly reduced in the EMD-10 (26.2% +/- 3.6%) and EMD-20 (22.5% +/- 2.4%) groups versus control (30.7% +/- 2.4%); however, infarct size was significantly reduced in the EMD-20R group (16.1% +/- 2.8%, p = 0.003). Edema in the area at risk in the EMD-10 (81.1% +/- 0.5% water content), EMD-20 (81.7% +/- 0.3%), and EMD-20R (81.9% +/- 0.3%) groups was less than in controls (83.2% +/- 0.2%), (p < 0.056). Neutrophil accumulation (myeloperoxidase activity) in postischemic area-at-risk myocardium was less in the EMD-20R group versus the control group (5.3 +/- 0.7 versus 8.7 +/- 1.4 absorbance units x min(-1) x g(-1); p = 0.05), which suggests an attenuated postischemic inflammatory response.


CONCLUSIONS
Optimal delivery of NHE1 inhibitor to the heart through combined cardioplegia and parenteral routes significantly attenuates myocardial injury after surgical reperfusion of regional ischemia. Timing, dose, and mode of delivery of NHE1 inhibitors are important to their efficacy.
Corvera
Joel S
JS
Cardiothoracic Research Laboratory, Emory University School of Medicine, Atlanta, Georgia, USA.
Zhao
Zhi-Qing
ZQ
Schmarkey
L Susan
LS
Katzmark
Sara L
SL
Budde
Jason M
JM
Morris
Cullen D
CD
Ehring
Thomas
T
Guyton
Robert A
RA
Vinten-Johansen
Jakob
J
D000704:Analysis of Variance; D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects* / Q000379:methods; D023921:Coronary Stenosis / Q000601:surgery; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006324:Heart Arrest, Induced; D006334:Heart Function Tests; D007262:Infusions, Intravenous; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D017923:Sodium-Hydrogen Exchangers / Q000008:administration & dosage*; D016896:Treatment Outcome
D017923:Sodium-Hydrogen Exchangers