PROTECTIVE EFFECTS OF DIMETHYL AMILORIDE AGAINST POSTISCHEMIC MYOCARDIAL DYSFUNCTION IN RABBIT HEARTS - PHOSPHORUS 31 NUCLEAR-MAGNETIC-RESONANCE MEASUREMENTS OF INTRACELLULAR PH AND CELLULAR-ENERGY

The effects of 5-(N,N-dimethyl)amiloride, a potent and specific Na+-H exchange inhibitor, were investigated in isolated perfused rabbit hea rts subjected to ischemia and reperfusion, Phosphorus 31-nuclear magne tic resonance spectroscopy was used to monitor intracellular pH, creat ine phosphate, beta-adenosine triphosphate, and inorganic phosphate. A fter cardioplegic arrest with St, Thomas' Hospital solution, normother mic (37 degrees C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10 mu mo l/L, which has minimal inotropic and chronotropic effects on the nonis chemic heart, was added to the cardioplegic solution, Treatment with d imethyl amiloride reduced the elevation of left ventricular end-diasto lic pressure during and after the ischemia and improved the postischem ic recovery of developed pressure from 76% +/- 3.2% at 30 minutes of r eperfusion in control hearts (n = 6) up to 99% +/- 1.9% in hearts trea ted 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 < 0.0 5), During reperfusion, inh acellular pH of hearts treated with dimeth yl amiloride was less than control for 5 minutes, but subsequent recov ery of intracellular pH was similar to control, Treatment with dimethy l amiloride did not affect creatine phosphate breakdown, inorganic pho sphate accumulation, and beta-adenosine triphosphate depletion during 45 minutes of ischemia, The creatine phosphate resynthesis and inorgan ic 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 po stischemic cardiac dysfunction most likely by inducing primary Na+ and secondary Ca2+ overload. Specific Na+-H+ exchange inhibitors like dim ethyl amiloride would have a potential therapeutic profile in cardiac surgery, especially if added before ischemia.