Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade.
We compared the protective effects of ischemic preconditioning (IPC) and the Na(+)/H(+) exchanger-1 (NHE-1) inhibitor cariporide in isolated rat hearts subjected to global ischemia (45 or 90 min) and 30-min reperfusion and determined the protective effects of cariporide under IPC blockade with the mitochondrial ATP-sensitive K(+) channel blocker 5-hydroxydecanoate (5-HD). With 45-min ischemia, both IPC and cariporide equally increased maximum recovery of left ventricular developed pressure twofold (P < 0.05), although recovery was significantly greater with cariporide for the first 15 min of reperfusion. 5-HD almost completely blocked the protective effects of IPC on recovery but had no influence on the salutary effects of cariporide. With 90-min ischemic control, recovery was only 3% of preischemia and was unaffected by IPC, although cariporide increased recovery to approximately 30% (P < 0.05). This was associated with a 37% preservation of viable cardiac cells, whereas no structurally intact cells were found in either IPC or control hearts. Our study shows that NHE-1 inhibition is a more effective cardioprotective strategy than IPC in this model, possibly because of enhanced myocyte salvage, and because protection by NHE-1 inhibition is completely unaffected by IPC blockade with 5-HD.
Haist
James V
JV
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Hirst
Claire N
CN
Karmazyn
Morris
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006146:Guanidines; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C052853:5-hydroxydecanoic acid; C093373:cariporide