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J Thorac Cardiovasc Surg 1996;112:765-775
© 1996 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

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

Received for publication July 24, 1995 Revisions requested Nov. 14, 1995; revisions received April 2, 1996 Accepted for publication April 3, 1996. Address for reprints: Itsuo Kodama, MD, Department of Humoral Regulation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-01, Japan.

Abstract

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,ß-adenosine triphosphate, and inorganic phosphate. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37º C) global ischemia was induced for 45 minutes, and the hearts were reperfused for 50 minutes. Dimethyl amiloride at 10µmol/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, andß–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. (J THORAC CARDIOVASC SURG 1996;112:765-75)

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