Extracorporeal Circulation Activates Endothelial Nitric Oxide Synthase in Erythrocytes

Background: Extracorporeal circulation used in cardiopulmonary bypass and hemodialysis is often associated with severe hypotension, which is an important predictor for mortality and morbidity. One pathophysiological hypothesis includes nitric oxide (NO) generation. Recently, a functional NO synthase (endothelial type NO synthase [eNOS]), was found to be expressed in human red blood cells. However, to date, activation of red blood cell eNOS has not been shown. We hypothesized that eNOS in circulating red blood cells might be activated during extracorporeal circulation and thus contribute to hypotension through vasodilation upon NO release.

Methods: We collected blood samples from 28 patients electively subjected to cardiac surgery during cardiopulmonary bypass (0, 20, 40, 60, and 80 minutes of cardiopulmonary bypass; taken for routine blood gas analyses). Red blood cells were immunohistochemically stained against activated eNOS. The degree of activation was assessed by television densitometry (gray units).

Results: We found significant red blood cell eNOS activation during cardiopulmonary bypass in a time dependent fashion. The eNOS activation occurred by dissociation of the enzyme from the cellular membrane into the cytosol (translocation). The correlation between activated eNOS and bypass duration was highly significant.

Conclusions: Red blood cells might contribute to hypotension through vasodilation upon NO release during extracorporeal circulation and could serve as new therapeutic targets in clinical practice.