The effects of
5-(N,N-dimethyl)amiloride, a potent and specific Na(+)-H+ exchange inhibitor, were investigated in isolated perfused rabbit hearts subjected to
ischemia and reperfusion.
Phosphorus 31-nuclear magnetic resonance spectroscopy was used to monitor intracellular pH,
creatine phosphate, beta-
adenosine triphosphate, and
inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital
solution, normothermic (37 degrees C) global
ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl
amiloride at 10 mumol/L, which has minimal inotropic and chronotropic effects on the nonischemic heart, was added to the
cardioplegic solution. Treatment with dimethyl
amiloride reduced the elevation of left ventricular end-diastolic pressure during and after the
ischemia and improved the postischemic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of reperfusion in control hearts (n = 6) up to 99% +/- 1.9% in hearts treated with dimethyl
amiloride (n = 8). Dimethyl
amiloride did not affect the decline in intracellular pH during
ischemia for up to 30 minutes but enhanced the intracellular
acidosis thereafter. The intracellular pH at the end of
ischemia was 6.21 +/- 0.05 in control hearts compared with 5.24 +/- 0.17 in hearts treated with dimethyl
amiloride (p < 0.05). During reperfusion, intracellular pH of hearts treated with dimethyl
amiloride was less than control for 5 minutes, but subsequent recovery of intracellular pH was similar to control. Treatment with dimethyl
amiloride did not affect
creatine phosphate breakdown,
inorganic phosphate accumulation, and beta-
adenosine triphosphate depletion during 45 minutes of
ischemia. The
creatine phosphate resynthesis and
inorganic phosphate reduction during reperfusion were also unaffected. These findings suggest that Na(+)-H+ exchange plays an important role not only during reperfusion but also during
ischemia for the development of postischemic cardiac dysfunction most likely by inducing primary Na+ and secondary Ca2+ overload. Specific Na(+)-H+ exchange inhibitors like dimethyl
amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before
ischemia.