Na+ overload during ischemia and reperfusion in rat hearts: comparison of the Na+/H+ exchange blockers EIPA, cariporide and eniporide.
Intracellular myocardial Na+ overload during ischemia is an important cause of reperfusion injury via reversed Na+/Ca2+ exchange. Prevention of this Na+ overload can be accomplished by blocking the different Na+ influx routes. In this study the effect of ischemic inhibition of the Na+/H+ exchanger (NHE) on [Na+]i, pH, and post-ischemic contractile recovery was tested, using three different NHE-blockers: EIPA, cariporide and eniporide. pHi and [Na+]i were measured using simultaneous 31P and 23Na NMR spectroscopy, respectively, in paced (5 Hz) isolated, Langendorff perfused rat hearts while contractility was assessed by an intraventricular balloon. NHE-blockers (3 microM) were administered during 5 min prior to 30 min of global ischemia followed by 30 min drug-free reperfusion. NHE blockade markedly reduced ischemic Na+ overload; after 30 min of ischemia [Na+]i had increased to 293 +/- 26, 212 +/- 6, 157 +/- 5 and 146 +/- 6% of baseline values in untreated and EIPA (p < 0.01 vs. untreated), cariporide (p < 0.01 vs. untreated) and eniporide (p < 0.01 vs. untreated) treated hearts, respectively. Ischemic acidosis did not differ significantly between groups. During reperfusion, however, recovery of pH, was significantly delayed in treated hearts. The rate pressure product recovered to 12.0 +/- 1.9, 12.1 +/- 2.1, 19.5 +/- 2.8 and 20.4 +/- 2.5 x 10(3) mmHg/min in untreated and EIPA, cariporide (p < 0.01 vs. untreated) and eniporide (p < 0.01 vs. untreated) treated hearts, respectively. In conclusion, blocking the NHE reduced ischemic Na+ overload and improved post-ischemic contractile recovery. EIPA, however, was less effective and exhibited more side effects than cariporide and eniporide in the concentrations used.
ten Hove
Michiel
M
Interuniversity Cardiology Institute of The Netherlands, Utrecht.
van Emous
Jan G
JG
van Echteld
Cees J A
CJ
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000737:chemistry; D006146:Guanidines / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007511:Ischemia; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010710:Phosphates / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D012964:Sodium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D010710:Phosphates; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D000584:Amiloride; C093373:cariporide; C118397:eniporide; D012964:Sodium; D002118:Calcium; C039614:ethylisopropylamiloride