Macromolecule Effects on Prostacyclin Production and Measurement

Incubation of human umbilical artery tissue in a crystalloid solution elicits the production of prostacyclin (PGI2). However, the inclusion of macromolecules in the incubation solution reduces the amount of PGI2 produced by the umbilical artery. This effect is independent of charge since serum proteins, polyglutamic acid, polylysine, or dextran all reduce PGI2 release by 50% at the same concentration of macromolecule (4.4 mg/ml). However, this effect is dependent on molecular size. Serum proteins with molecular weights (MW) below 60,000 are less effective than serum proteins above 60,000 MW (excluding albumin), and dextrans of 10,000 and 40,000 MW are not effective whereas dextrans of 70,000 and 500,000 MW are effective in reducing PGI2 release. The effective macromolecules act at the exterior surface of the cell and do not shunt arachidonic acid into other catabolic pathways. Although the presence of these macromolecules affects the radioimmunoassay measurement of 6-keto-PGF1α, this effect can be quantitatively accounted for and does not explain the observed reduction in PGI2 release. These studies appear to demonstrate a connection between receptor-independent cell surface events (adhesion of macromolecules) and the initiation of intracellular enzymatic activity (PGI2 production). We hypothesize that macromolecules associate with the cell surface and retard the lateral mobility of externally projecting cell surface components. This would decrease the formation of cell membrane complexes responsible for arachidonic acid release. The observed reduction in PGI2 release would result, then, from decreased precursor arachidonic acid release. Thus, the presence of macromolecules at the cell surface decreases the cellular response (e.g., prostaglandin production) to membrane perturbations and represents the in vivo situation. This may be an important consideration clinically (e.g., the choice between colloid or crystalloid solution for infusion) when increased prostaglandin release would be deleterious to the patient.