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

被引:112
作者
Gumina, RJ
Buerger, E
Eickmeier, C
Moore, J
Daemmgen, J
Gross, GJ
机构
[1] Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA
[2] Boehringer Ingelheim Pharma KG, Ingelheim, Germany
关键词
myocardial infarction; ions; ischemia;
D O I
10.1161/01.CIR.100.25.2519
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 I 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 LPC, BIIB 0.75 mg/kg was administered either before LPC or during the washout phase of TPC 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 TPC or that different mechanisms are involved in the cardioprotective effect of IPC and NHE-1 inhibition.
引用
收藏
页码:2519 / 2526
页数:8
相关论文
共 35 条
[1]   THE BINDING-SITE FOR [H-3] GLIBENCLAMIDE IN THE RAT CEREBRAL-CORTEX DOES NOT RECOGNIZE K-CHANNEL AGONISTS OR ANTAGONISTS OTHER THAN SULFONYLUREAS [J].
ANGEL, I ;
BIDET, S .
FUNDAMENTAL & CLINICAL PHARMACOLOGY, 1991, 5 (02) :107-115
[2]  
BROWN GB, 1986, J NEUROSCI, V6, P2064
[3]  
BUGGE E, 1995, CARDIOVASC RES, V29, P269, DOI 10.1016/0008-6363(96)88580-4
[4]  
CATTERALL WA, 1979, J BIOL CHEM, V254, P1379
[5]  
COUNILLON L, 1993, MOL PHARMACOL, V44, P1041
[6]  
COUNILLON L, 1995, CARDIOVASC RES, V29, P147, DOI 10.1016/0008-6363(96)88562-2
[7]  
FRANCHI A, 1986, J BIOL CHEM, V261, P4614
[8]   SEPARATION OF OVERLAP AND COLLATERAL PERFUSION OF ISCHEMIC CANINE MYOCARDIUM - IMPORTANT CONSIDERATIONS IN THE ANALYSIS OF VASODILATOR-INDUCED CORONARY STEAL [J].
GROSS, GJ ;
BUCK, JD ;
WARLTIER, DC ;
HARDMAN, HF .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1982, 4 (02) :254-263
[9]   BLOCKADE OF ATP-SENSITIVE POTASSIUM CHANNELS PREVENTS MYOCARDIAL PRECONDITIONING IN DOGS [J].
GROSS, GJ ;
AUCHAMPACH, JA .
CIRCULATION RESEARCH, 1992, 70 (02) :223-233
[10]  
Gumina RJ, 1998, J PHARMACOL EXP THER, V286, P175