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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1103-1108
PLENARY PAPER
Arginine supplementation of sickle transgenic mice reduces red
cell density and Gardos channel activity
José R. Romero,
Sandra M. Suzuka,
Ronald L. Nagel, and
Mary E. Fabry
From the Endocrine-Hypertension Division, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA; and Division of
Hematology, Albert Einstein College of Medicine, Montefiore Medical
Center, Bronx, NY.
Nitric oxide (NO), essential for maintaining vascular tone,
is produced from arginine by nitric oxide synthase. Plasma arginine levels are low in sickle cell anemia, and it is reported here that low plasma arginine is also found in our sickle transgenic mouse
model that expresses human  , human  S, and human
S-Antilles and is homozygous for the mouse
major deletion (S+S-Antilles). S+S-Antilles mice were
supplemented with a 4-fold increase in arginine that was maintained for
several months. Mean corpuscular hemoglobin concentration (MCHC)
decreased and the percent high-density red cells was reduced. Deoxy
K+ efflux is characteristic of red cells in sickle cell
disease and contributes to the disease process by increasing the MCHC and rendering the cells more susceptible to polymer formation. This
flux versus the room air flux was reduced in S+S-Antilles red cells
from an average value of 1.6 ± 0.3 mmol per liter of red cells × minute (FU) in nonsupplemented mice to 0.9 ± 0.3 FU (n = 4, P < .02, paired t test) in
supplemented mice. In room air, Vmax of the
Ca++-activated K+ channel (Gardos) was reduced
from 4.1 ± 0.6 FU (off diet) to 2.6 ± 0.4 FU (n = 7 and 8, P < .04, t test) in arginine-supplemented mice versus clotrimazole. In conclusion, the major mechanism by which
arginine supplementation reduces red cell density (MCHC) in
S+S-Antilles mice is by inhibiting the Ca++-activated
K+ channel.
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