Influence of pH on the rheologic and antisickling effects of dimethyl adipimidate

Dimethyl adipimidate, a bifunctional imidoester, is an effective inhibitor of sickling in vitro. We determined the reaction conditions necessary to inhibit sickling without impairing cell deformability. Although imidoesters are routinely used at alkaline pH, we found that reaction of red blood cells with dimethyl adipimidate at pH 8.4 shortened the survival of rat red blood cells and impaired the deformability of human red blood cells. These adverse effects were eliminated by changing the pH of the reaction from 8.4 to 7.4. Furthermore, treatment of sickle cells with dimethyl adipimidate at pH 7.4 inhibited sickling, as demonstrated by dose-dependent reductions in the percentage of sickle forms, viscosity, and potassium efflux. Dimethyl adipimidate appeared to inhibit sickling by several mechanisms: namely, it increased deoxygenated sickle hemoglobin solubility, oxygen affinity, and cell hydration. We conclude that dimethyl adipimidate at pH 7.4 can inhibit sickling without impairing the rheologic properties of the red blood cell.