Effect of methylisobutyl amiloride on [Na+]i, reperfusion arrhythmias, and function in ischemic rat hearts.
With 2 microM methylisobutyl amiloride (MIA), an inhibitor of Na+/H+ exchange, we tested the hypothesis that ion imbalance due to H+/Na+/Ca2+ exchange exacerbates reperfusion injury and arrhythmias. Isolated rat hearts were subjected to 25-min global ischemia and 30-min reperfusion. In the MIA-treated group, MIA was added throughout the perfusion protocol. Left ventricular pressure (LVP), arrhythmias, myocardial Na+ and K+ content, 45Ca2+ uptake, and the levels of energy metabolites were analyzed. The recovery of LV developed pressure (LVDP) and +dP/dt and -dP/dt were improved in the MIA group (53 vs. 80, 71 vs. 86, 77 vs. 94%: each p < 0.05). MIA inhibited the increase in Na+ content and the decrease in K+ content that occurred at the end of the ischemic phase and reduced 45Ca2+ uptake after reperfusion (28.6 vs. 17.1, 248 vs. 296, 2.79 vs. 1.36 microM/g dry weight of tissue; each p < 0.05). The incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) was lower in the MIA group [VT 11 of 20 (55%) vs. 4 of 20 (20%), p < 0.05; VF 13 of 20, (65%) vs. 6 of 20 (30%), 0.05 < p < 0.1], although the incidence of VF just escaped statistical significance. ATP level was higher in the MIA group after the ischemic phase and reperfusion (5.3 vs. 9.9, 12.3 vs. 14.7 microM/g dry weight of tissue; each p < 0.05). Our results suggest that MIA reduced reperfusion arrhythmias and improved functional recovery in isolated rat hearts subjected to global ischemia apparently by preserving high-energy phosphates during ischemia and by inhibiting Na+/H+ exchange, with attenuated cellular imbalance between Na+ and Ca2+.
Tani
M
M
Department of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan.
Shinmura
K
K
Hasegawa
H
H
Nakamura
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D016277:Ventricular Function, Left
D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D000255:Adenosine Triphosphate; C056369:5-(N-methyl-N-isobutyl)amiloride; D012964:Sodium; D002118:Calcium