Related Experiment Videos
Inhibition of erythrocyte calcium transport by cetiedil
S N Levine1, L R Berkowitz, E P Orringer
1Department of Medicine, Louisiana State University Medical Center, Shreveport.
Insights
Cetiedil protects red blood cells from high calcium levels in sickle cell anemia by inhibiting calmodulin-stimulated calcium transport and enzyme activity. This mechanism, not by lowering calcium, likely underlies its beneficial antisickling effects.
Area of Science:
- Hematology
- Biochemistry
- Pharmacology
Background:
- Elevated red blood cell calcium is implicated in sickle cell anemia pathogenesis, including hemolysis and vasoocclusion.
- Cetiedil, an antisickling agent, is known to inhibit calmodulin-stimulated enzymes.
Purpose of the Study:
- To elucidate the mechanism of cetiedil's action on calcium-mediated erythrocyte function.
- To investigate cetiedil's effect on calcium transport and key enzyme activities (phosphodiesterase, Ca-ATPase) in erythrocytes.
Main Methods:
- Examined the effect of cetiedil on active calcium transport into inside-out erythrocyte vesicles.
- Assessed the influence of cetiedil on calmodulin-stimulated phosphodiesterase and Ca-ATPase activities.
- Compared effects in erythrocytes from normal controls and sickle cell anemia patients.
Main Results:
- Cetiedil significantly inhibited calmodulin-dependent calcium transport into vesicles from both normal and sickle cell erythrocytes.
- No inhibition of calcium transport was observed in the absence of calmodulin.
- Cetiedil specifically inhibited calmodulin-stimulated, but not basal, phosphodiesterase and Ca-ATPase activities.
Conclusions:
- Cetiedil's beneficial effect in sickle cell anemia is unlikely due to a reduction in intracellular calcium content.
- The drug's protective action likely stems from mitigating the adverse effects of high intracellular calcium concentrations on red blood cells.
- Cetiedil's mechanism involves interfering with calmodulin-mediated calcium signaling pathways within erythrocytes.
Abstract:
The elevated calcium content found in red cells from patients with sickle cell anemia may be of pathophysiologic importance in the hemolysis and vasoocclusion which characterize this disorder. Cetiedil, an antisickling agent, has been reported to inhibit the activity of enzymes that are stimulated by the calcium regulatory protein calmodulin. To investigate the mechanism by which cetiedil modifies calcium-mediated erythrocyte function, the effect of the drug on the active transport of calcium into inside-out erythrocyte vesicles was examined and its influence on the activities of phosphodiesterase and Ca-ATPase studied. Cetiedil, in the presence of calmodulin, significantly inhibited calcium transport into inside-out vesicles that were prepared with erythrocytes from normal controls and from patients with sickle cell anemia. However, in the absence of calmodulin, no inhibition was observed. Likewise, cetiedil inhibited calmodulin-stimulated, but not basal, activities of phosphodiesterase and Ca-ATPase. These data, along with previous reports, suggest that cetiedil does not act by lowering the intracellular calcium content. It is, therefore, likely that the beneficial effect of cetiedil is due to its ability to protect the red cell from the deleterious consequences of an elevated concentration of intracellular calcium.