Pharmacological modification of oxygen affinity improves deformability of deoxygenated sickle erythrocytes: a possible therapeutic approach to sickle cell disease.
1. The formation of polymerized haemoglobin S in sickle cells is critically dependent on the concentration of deoxygenated haemoglobin so that compounds which increase the oxygen affinity of haemoglobin S are potential anti-sickling agents. 2. BW12C [5-(2-formyl-3-hydroxyphenoxy)pentanoic acid] and BWA589C [4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid] are aromatic benzaldehydes that cause a dose-dependent left-shift of the oxygen saturation curve of haemoglobin S by stabilization of its oxy-(R)-conformation. 3. A 5 micron pore filtration method, which is highly sensitive to polymerization of haemoglobin S, was used to demonstrate a significant improvement in the deformability of deoxygenated sickle erythrocytes at concentrations (0.75-1.5 mmol/l] of BW12C and BWA589C that are achievable in vivo. Both compounds may therefore be of value for the treatment of sickle cell disease. 4. Filtration of sickle cells through pores of 5 microns diameter is a sensitive technique for evaluating the rheological effects of potential anti-sickling compounds.
Keidan
A J
AJ
Department of Haematology, Medical School, University of Birmingham, U.K.
Sowter
M C
MC
Johnson
C S
CS
Marwah
S S
SS
Stuart
J
J
D000755:Anemia, Sickle Cell / Q000097:blood / Q000378:metabolism / Q000628:therapy*; D001547:Benzaldehydes / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004907:Erythrocyte Deformability / Q000187:drug effects*; D006451:Hemoglobin, Sickle; D006801:Humans; D010100:Oxygen / Q000378:metabolism*
D001547:Benzaldehydes; D001565:Benzoates; D006451:Hemoglobin, Sickle; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid; C059629:tucaresol; D010100:Oxygen