Faculty Collaboration Database

Inhibition of the Na(+)/H(+) exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs. Circulation 1999 Dec 21-28;100(25):2519-26; discussion 2469-72

Date

12/22/1999

Pubmed ID

10604890

DOI

10.1161/01.cir.100.25.2519

Scopus ID

2-s2.0-0033613553 (requires institutional sign-in at Scopus site)   121 Citations

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.

Author List

Gumina RJ, Buerger E, Eickmeier C, Moore J, Daemmgen J, Gross GJ

MESH terms used to index this publication - Major topics in bold

Amiloride
Animals
Dogs
Drug Evaluation, Preclinical
Guanidines
Hemodynamics
Hydrogen
Ion Transport
Ischemic Preconditioning, Myocardial
Mesylates
Muscle Proteins
Myocardial Infarction
Myocardial Reperfusion Injury
Sodium
Sodium-Hydrogen Exchangers
Sulfones