Aggregation of Red Cells and Effects of Nonsteroidal Anti-inflammatory Drugs

Summary and Discussion

Carrageenan, dextran, phytohemagglutinin-P, alpha-amylase, acid phosphatase, polycytidylic acid, polyadenylic acid, polygalacturonic acid, poly-L-proline, poly-L-glutamic acid and others promote red cell sedimentation rates (ESR) when added to washed red cells. Rabbit antisera to red cells and serum promote the ESR when added to either whole blood or washed red cells. All of these various acceleratory responses, with the exception of those induced by enzymes, are inhibited by nonsteroidal anti-inflammatory drugs (NAIFD). Many other pharmacologic classes, with the exception of ethacrynic acid, probenecid, sodium cromoglycate and chlorothiazide, fail to display similar inhibitory effects. The elevated ESR is inhibited when drugs are added before, during, or after the addition of dextran. The ESR is inhibited by 2, 4-dinitrophenol, but not other metabolic inhibitors. Heavy metal ions and anerobiosis have no effect on dextran-induced ESR.

Agents accelerating the ESR induce acute inflammatory responses when inoculated locally into the hindpaws of rats.

Drugs whose inhibitory effects are less readily removed from dextran-treated red cells by repeated saline washings, e.g., indomethacin, have longer durations of action when tested in acute inflammatory reactions of intact animals against salicylic acid whose effects are removed more rapidly.

Mechanisms of action of accelerators or inhibitors of the ESR are unknown. The NAIFD are, for the most part, acidic. They may adhere to available positive charges on damaged or altered cell membranes and prevent their tendency to “stick,” adhere, aggregate, clump or pull together.

Although red cell aggregation is among the many convenient models for the assessment in vitro of well-known NAIFD, it fails, like many other isolated methods (3-5), to have predictive value for unknown agents. Many undisclosed chemical agents have been discovered to be extremely potent in the isolated ESR system. When given subsequently at varying dosages and routes of administration to animals, however, they fail (in our hands, at least) to display “anti-inflammatory” activity.

The dextran- and carrageenan-induced ESR appears to be a rather specific method for screening NAIFD discovered by other methods and for the study of their probable mechanisms of action.