Myocardial dysfunction is associated with activation of Na+/H+ exchange immediately during reperfusion.
Amiloride analogs block Na+/H+ exchange and thereby protect the heart from myocardial ischemia-reperfusion injury. It is unclear whether drugs must be present before ischemia to be cardioprotective. After 60 min of global ischemia in the coronary-perfused right ventricular wall (RVW), as little as 1 min of exposure to dimethyl amiloride (DMA) immediately at the time of reperfusion protected the RVW. Delaying the drug attenuated the cardioprotection. If DMA was introduced in an ischemic solution near the end of ischemia, the cardioprotective effects were augmented. If the drug was washed out of the RVW vascular space before ischemia, cardioprotection was not observed. In contrast, in whole hearts, preischemic perfusion of the drug was necessary for cardioprotection and the cardioprotection remained even if the drug was washed out before ischemia. We conclude that Na+/H+ exchange is active and contributes to contractile dysfunction during the first seconds of reperfusion. This is difficult to detect in the perfused whole heart, and the washout data suggest that this may be due to a limitation in drug delivery across the vascular wall. The data also suggest that the exchanger is not as active during ischemia itself as it is during reperfusion.
Maddaford
T G
TG
Ion Transport Laboratory, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Pierce
G N
GN
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013997:Time Factors; D018754:Ventricular Dysfunction / Q000503:physiopathology; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
D002316:Cardiotonic Agents; D017923:Sodium-Hydrogen Exchangers; C039465:5-dimethylamiloride; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride