Protective effect of the sodium/hydrogen exchange inhibitors during global low-flow ischemia.
We investigated the potential role of the Na+/H+ exchanger (NHE) during global low-flow ischemia. Isolated working rat hearts were subjected to a low-flow ischemic period of 30 or 60 min at 37 degrees C and then reperfused for 30 min. Under those conditions, the effects of two NHE inhibitors 3-methylsulphonyl-4-piperidinobenzoyl guanidine methanesulphonate (HOE-694, 1 microM) and 5-(N-ethyl-N-isopropyl) amiloride (EIPA, 1 microM), were compared. When added to the perfusion fluid 15 min before induction of ischemia, EIPA partially preserved aortic output (AO) during either a 30- or 60-min low-flow period. A lesser effect, which was not statistically significant, was observed with HOE-694. Therefore, after 30-min ischemia, AO was 18.7 +/- 2.7, 31.4 +/- 3.3% (p < 0.05 vs. control group) and 25.8 +/- 3.2% of the preischemic value in control and EIPA- and HOE-694-treated groups, respectively. Similarly, after 60-min low-flow ischemia, AO was 15.7 +/- 1.8, 32.7 +/- 4.2% (p < 0.05 vs. control group) and 23.3 +/- 5.6% in control and EIPA- and HOE-694-treated groups, respectively. When EIPA and HOE-694 were added to the perfusion solution during the 60-min ischemic period, i.e., at 15 min of low-flow ischemia, AO was maintained at 38.9 +/- 4.9 and 30.2 +/- 2.4% (vs. 15.7 +/- 1.8% in the controls) in HOE-694- and EIPA-treated groups, respectively. EIPA but not HOE-694 also significantly (p < 0.05) improved the AO recovery during reperfusion. When administered later during ischemia, EIPA but not HOE-694 caused some recovery of AO during the remainder of the ischemic period but did not aid recovery during reperfusion. Our data suggest that although inhibition of NHE may be of some benefit during low-flow ischemia, additional effects may be necessary to provide a more efficient cardioprotection. An additional action, e.g., inhibition of the Na+/HCO3- cotransporter, could explain the superior effect of EIPA with respect to HOE-694.
SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France.
N
N
Khandoudi
M P
MP
Laville
A
A
Bril
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D000584:Amiloride; C039614:ethylisopropylamiloride