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 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.
Koike
A
A
Department of Thoracic Surgery, School of Medicine, Nagoya University, Japan.
Akita
T
T
Hotta
Y
Y
Takeya
K
K
Kodama
I
I
Murase
M
M
Abe
T
T
Toyama
J
J
D000138:Acidosis / Q000503:physiopathology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000584:Amiloride / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001639:Bicarbonates; D002118:Calcium / Q000378:metabolism; D002122:Calcium Chloride; D002314:Cardioplegic Solutions; D003971:Diastole; D004734:Energy Metabolism; D006321:Heart / Q000187:drug effects*; D006324:Heart Arrest, Induced; D006863:Hydrogen-Ion Concentration; D007511:Ischemia; D008274:Magnesium; D009682:Magnetic Resonance Spectroscopy; D009200:Myocardial Contraction / Q000187:drug effects; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D010759:Phosphorus Isotopes; D011189:Potassium Chloride; D011817:Rabbits; D012964:Sodium / Q000378:metabolism; D012965:Sodium Chloride; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D001639:Bicarbonates; D002314:Cardioplegic Solutions; D010710:Phosphates; D010759:Phosphorus Isotopes; D017923:Sodium-Hydrogen Exchangers; C041711:St. Thomas' Hospital cardioplegic solution; D010725:Phosphocreatine; C039465:5-dimethylamiloride; D012965:Sodium Chloride; D011189:Potassium Chloride; D000584:Amiloride; D000255:Adenosine Triphosphate; D012964:Sodium; D008274:Magnesium; D002122:Calcium Chloride; D002118:Calcium