HYPERCAPNIC ACIDOSIS AND DIMETHYL AMILORIDE REDUCE REPERFUSION-INDUCED CELL-DEATH IN ISCHEMIC VENTRICULAR MYOCARDIUM

Objective: The aim was to investigate the effects of slowing the recov ery of ischaemia induced intracellular acidosis with hypercapnic acido sis or dimethyl amiloride (DMA) on the extent of reperfusion induced c ell death. Methods: Isolated arterially perfused rabbit papillary musc les and septa were suspended in a controlled atmosphere and perfused w ith a modified Tyrode solution containing erythrocytes and trypan blue (500 mu M). Ischaemia was produced by arrest of perfusion and withdra wl of atmospheric O-2. Extracellular pH of the muscle during reperfusi on was controlled by adjusting the pH of the perfusate (pH 6.6 or pH 7 .6 with and without DMA 20 mu M) and changing the PCO2 Of the chamber atmosphere. After 30 min of reperfusion following 30 min (group A) or 60 min (group B) of ischaemia, papillary muscles were fixed with paraf ormaldehyde. Cell death was assessed by trypan blue staining of nuclei in histological sections of the papillary muscles. Results: The magni tude of cell death was greatest after reperfusion with pH 7.6 as measu red by the percentage of nuclei staining with trypan blue (15.1% in gr oup A; 41.8% in group B). By contrast, reperfusion at pH 6.6 reduced c ell killing (group A, 3.6%; group B, 7.2%). Reperfusion at pH 7.6 with DMA (20 mu M) also reduced trypan blue uptake (group A, 2.8%; group B , 3.8%). Despite the attenuation of cell death afforded by acidosis or Na+/H+ exchange inhibition, significant swelling of the extracellular space and microvascular injury was noted. Conclusions: Hypercapnic ac idosis and Na+/H+ exchange inhibition during reperfusion attenuate let hal reperfusion injury to ventricular myocardium and extend to the int act myocardium the concept of the ''pH paradox'' in which recovery of intracellular pH after reperfusion is a precipitating factor in lethal cell injury.