title: Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity.
abstract: 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 alpha, human beta(S), and human beta(S-Antilles) and is homozygous for the mouse beta(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 x minute (FU) in nonsupplemented mice to 0.9 +/- 0.3 FU (n = 4, P < .02, paired t test) in supplemented mice. In room air, V(max) 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.
authors.affiliation: Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Romero
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Suzuka
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Nagel
authors.forename: Mary E
authors.initials: ME
authors.lastname: Fabry
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002956:Citrulline / Q000097:blood; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects*; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D024681:Potassium Channels, Calcium-Activated; D002956:Citrulline; D001120:Arginine; D011188:Potassium; D010100:Oxygen