Additive in vitro effects of anti-sickling drugs.
To study the effect of anti-sickling drugs on cellular dehydration induced by entry of Ca, sickle cells were subjected to cyclical oxygenation-deoxygenation for 15 h in Ca-containing buffer. The consequential loss of cation (K) via the Ca-dependent K efflux (Gardos) channel caused cell dehydration and loss of deformability. Inhibition of a specific fraction of Ca entry by verapamil had no rheologically protective effect, whereas inhibition of the Gardos channel by clotrimazole or nitrendipine had a marked protective effect. When Gardos channel inhibition (by either clotrimazole or nitrendipine) was combined with stabilization of the oxy-conformation of sickle haemoglobin (by the substituted benzaldehyde 12C79), an additive protective rheological effect was achieved with 60-78% reduction in clogging rate of 5 microns diameter pores when compared with no drug. Therapeutic use of anti-sickling compounds in combination may achieve increased efficacy with lower toxicity.
Stuart
J
J
Department of Haematology, Medical School, University of Birmingham.
Mojiminiyi
F B
FB
Stone
P C
PC
Culliford
S J
SJ
Ellory
J C
JC
D000755:Anemia, Sickle Cell / Q000097:blood*; D000986:Antisickling Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D003022:Clotrimazole / Q000494:pharmacology; D004357:Drug Synergism; D004907:Erythrocyte Deformability / Q000187:drug effects; D004909:Erythrocyte Indices / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D018056:Hemorheology / Q000187:drug effects*; D006801:Humans; D009568:Nitrendipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D011188:Potassium / Q000097:blood; D015221:Potassium Channels / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D000986:Antisickling Agents; D001547:Benzaldehydes; D015221:Potassium Channels; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid; D009568:Nitrendipine; D014700:Verapamil; D003022:Clotrimazole; D011188:Potassium; D002118:Calcium