Inhibition of the Na(+)/H(+) exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs.

Abstract

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.

METHODS AND 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.

• Authors: R J Gumina, E Buerger, C Eickmeier, J Moore, J Daemmgen, G J Gross
• Journal: Circulation (Circulation) 1999 Dec 21-28 Vol. 100 Issue 25 Pg. 2519-26; discussion 2469-72 ISSN: 0009-7322 [Print] United States
• PMID: 10604890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Guanidines
• Mesylates
• Muscle Proteins
• Sodium-Hydrogen Exchangers
• Sulfones
• Amiloride
• cariporide
• Hydrogen
• Sodium
• BIIB 513
• ethylisopropylamiloride

Topics

• Amiloride (analogs & derivatives, pharmacology)
• Animals
• Dogs
• Drug Evaluation, Preclinical
• Guanidines (pharmacology)
• Hemodynamics
• Hydrogen (metabolism)
• Ion Transport (drug effects)
• Ischemic Preconditioning, Myocardial
• Mesylates (pharmacology, therapeutic use)
• Muscle Proteins (antagonists & inhibitors)
• Myocardial Infarction (drug therapy, therapy)
• Myocardial Reperfusion Injury (drug therapy, prevention & control, therapy)
• Sodium (metabolism)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Sulfones (pharmacology)