Enhanced Na+/H+ exchange during ischemia and reperfusion impairs mitochondrial bioenergetics and myocardial function.
Inhibition of Na+/H+ exchange (NHE) during ischemia reduces cardiac injury due to reduced reverse mode Na+/Ca2+ exchange. We hypothesized that activating NHE-1 at buffer pH 8 during ischemia increases mitochondrial oxidation, Ca2+ overload, and reactive O2 species (ROS) levels and worsens functional recovery in isolated hearts and that NHE inhibition reverses these effects. Guinea pig hearts were perfused with buffer at pH 7.4 (control) or pH 8 +/- NHE inhibitor eniporide for 10 minutes before and for 10 minutes after 35- minute ischemia and then for 110 minutes with pH 7.4 buffer alone. Mitochondrial NADH and FAD, [Ca2+], and superoxide were measured by spectrophotofluorometry. NADH and FAD were more oxidized, and cardiac function was worse throughout reperfusion after pH 8 versus pH 7.4, Ca2+ overload was greater at 10-minute reperfusion, and superoxide generation was higher at 30-minute reperfusion. The pH 7.4 and eniporide groups exhibited similar mitochondrial function, and cardiac performance was most improved after pH 7.4+eniporide. Cardiac function on reperfusion after pH 8+eniporide was better than after pH 8. Percent infarction was largest after pH 8 and smallest after pH 7.4+eniporide. Activation of NHE with pH 8 buffer and the subsequent decline in redox state with greater ROS and Ca2+ loading underlie the poor functional recovery after ischemia and reperfusion.
Aldakkak
Mohammed
M
Anesthesiology Research Laboratories, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Stowe
David F
DF
Heisner
James S
JS
Spence
Marisha
M
Camara
Amadou K S
AK
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D008929:Mitochondria, Heart / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013450:Sulfones / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D006146:Guanidines; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D009243:NAD; D013481:Superoxides; D005182:Flavin-Adenine Dinucleotide; C118397:eniporide; D002118:Calcium