One of the early sequelae of ischemia is an increase of circulating lactic acid that occurs in response to anaerobic metabolism. The purpose of the present study was to investigate whether lactic acidosis can induce endothelial swelling in vitro under closely controlled extracellular conditions. Cell volume of suspended cultured bovine aortic endothelial cells was measured by use of an advanced Coulter technique employing the “pulse area analysis” signal-processing technique (CASY1). The isosmotic reduction of pH from 7.4 to 6.8 had no effect on cell volume. Lowering of pH to 6.6, 6.4, or 6.0, however, led to significant, pH-dependent increases of cell volume. Swelling was more pronounced in bicarbonate-buffered media than in HEPES buffer. Specific inhibition of Na+/H+exchange by ethylisopropylamiloride completely prevented swelling in HEPES-buffered media. Pretreatment with ouabain to partially depolarize the cells did not affect the degree of acidosis-induced swelling. In bicarbonate-buffered media, the inhibition of transmembrane HCO3 − transport by DIDS reduced swelling to a level comparable with that seen in the absence of bicarbonate ions. Lactacidosis-induced endothelial swelling, therefore, is a result of intracellular pH regulatory mechanisms, namely, Na+/H+ exchange and bicarbonate-transporting carriers.
Endothelial swelling can be expected to occur in severely ischemic tissue sections and may then advance no-reflow. Therapeutic strategies should be established to prevent acidosis-induced endothelial swelling, e.g., by specific antagonists of the transport systems involved, or to reduce swelling by osmotic treatment such as hypertonic-hyperoncotic solutions.
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