Arginine supplementation improves the hydration of sickle cells in a mouse model

The polymerization rate of sickle hemoglobin (HbS) is exquisitely sensitive to its concentration. Since the amount of HbS in a sickle cell is essentially fixed, the concentration is determined by cell volume, which in turn depends on the cellular content of monovalent cations. Sickle cells tend to become potassium depleted, leading to dehydration and increased polymerization and sickling. These observations made apparent the need to understand the cation transport properties of sickle cells, and it is now generally agreed that there are 3 major contributors: KCl cotransport, sickling-induced permeability, and the calcium-activated K channel (also called the Gardos channel in red cells).

Romero and colleagues (page 1103) have shown, in a mouse model of sickle cell disease, that dietary arginine supplementation leads to correction of low plasma arginine levels and partial normalization of red cell hydration, with fewer dense, dehydrated cells. It seems likely that this beneficial effect on cell hydration was a consequence of decreased calcium-activated K-channel activity, since in the arginine-supplemented group this transporter was shown to have a lower activity after stimulation by ionophore-mediated calcium entry. Potassium efflux during deoxygenation in the presence of calcium was also decreased and was most likely also due to inhibition of the calcium-activated K channel. But an effect on sickling-induced permeability, which is thought to be responsible for calcium entry into the sickle cell, cannot be ruled out. There was no change in the reticulocyte count after arginine supplementation, which was disappointing in light of the decreased K-channel activity and normalized cell density.

The potential significance of these results is increased by reports of low plasma arginine in patients with sickle cell disease. Further investigations are clearly needed to examine the mechanism by which arginine influences red cell cation transport.