Inhibition of the Na(+)/H(+) exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs.
BACKGROUND
This study compared the efficacy of ischemic preconditioning (IPC) and sodium-hydrogen exchanger (NHE)-1 inhibition to reduce infarct size (IS) induced by a 90-minute ischemic insult and examined the interaction between NHE-1 inhibition and IPC.


RESULTS
In a canine infarct model, either IPC, produced by 1 or four 5-minute coronary artery occlusions, or the specific NHE-1 inhibitor BIIB 513, 0.75 or 3.0 mg/kg, was administered 15 minutes before either a 60- or 90-minute coronary artery occlusion followed by 3 hours of reperfusion. IS was determined by TTC staining and expressed as a percentage of the area at risk (IS/AAR). Although both IPC and BIIB 513 at 0.75 mg/kg produced comparable and significant reductions in IS/AAR in the 60-minute occlusion model, insignificant reductions in IS/AAR were observed in the 90-minute occlusion model. However, BIIB 513 at 3.0 mg/kg markedly reduced IS in both models (P<0.05). Next, to examine the interaction between NHE-1 blockade and IPC, BIIB 0.75 mg/kg was administered either before IPC or during the washout phase of IPC before 90 minutes of coronary artery occlusion. Both combinations resulted in a greater-than-additive reduction in IS/AAR (P<0.05).


CONCLUSIONS
These data demonstrate that although IPC and NHE-1 inhibition provide comparable protection against 60 minutes of myocardial ischemia, NHE-1 inhibition is more efficacious than IPC at protecting against a 90-minute ischemic insult. Furthermore, the combination of NHE-1 inhibition and IPC produces a greater-than-additive reduction in IS/AAR, suggesting either that NHE activity limits the efficacy of IPC or that different mechanisms are involved in the cardioprotective effect of IPC and NHE-1 inhibition.
Gumina
R J
RJ
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
Buerger
E
E
Eickmeier
C
C
Moore
J
J
Daemmgen
J
J
Gross
G J
GJ
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics; D006859:Hydrogen / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008698:Mesylates / Q000494:pharmacology / Q000627:therapeutic use*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control* / Q000628:therapy; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology
D006146:Guanidines; D008698:Mesylates; D009124:Muscle Proteins; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D000584:Amiloride; C093373:cariporide; D006859:Hydrogen; D012964:Sodium; C402725:BIIB 513; C039614:ethylisopropylamiloride