The first quantitative findings on the energy metabolism of human immune cells are presented. In quiescent peripheral blood mononuclear cells (PBMC) protein biosynthesis and Na+,K+-ATPase activity each accounted for 8% of cellular oxygen consumption. Stimulation with 25, 50, and 75 microg Con A/ml (1.25, 2.5 or 3.75 microg/10(6) cells) increased total oxygen consumption within seconds by 8, 36, and 53%, respectively. After addition of 75 microg Con A/ml, the proportion of cellular oxygen consumption due to protein biosynthesis, Na+,K+-ATPase activity, and Ca2+-ATPase activity was 15% each and that due to DNA/RNA synthesis was 8%. On the basis of these findings the immediate effects of five different glucocorticoids on cellular energy metabolism were investigated. The various glucocorticoids exerted basically the same inhibitory effects on Con A-stimulated cellular respiration and individual ATP-consuming processes, but differed significantly in potency. Similar to previous studies on rat thymocytes, the relative potencies of the glucocorticoids were found to be: prednylidene (1.7) > dexamethasone (1.5) > methylprednisolone (1.0) > prednisolone (0.3) > betamethasone (< 0.2). Given their rapidity of onset, these effects must be nongenomically mediated. The differences between the relative potencies of the various glucocorticoids for these effects and those for the classical genomic effects have important clinical implications, in particular for high-dose systemic and local glucocorticoid therapy.

Two groups of antioxidant compounds, the 21-aminosteroids and the pyrrolopyrimidines, have been found to act as neuroprotective drugs against lipid peroxidation in the injured CNS. Like glucocorticoids at high doses they are assumed to produce their effects at least in part by direct membrane stabilizing effects. In order to prove this hypothesis, we have investigated in this study the effects of these drugs on the energy metabolism of activated human peripheral blood mononuclear cells (PBMC) since these cells have been shown to serve as a suitable test system for substances affecting processes of ATP turnover. We compared the in vitro effects of (i) the 21-aminosteroid lazaroid tirilazad, (ii) the pyrrolopyrimidine lazaroid PNU-101033E and (iii) the glucocorticoid methylprednisolone on mitogen-induced respiration rate and ATP-consumption. We show that tirilazad inhibits concanavalin A-stimulated respiration rate and sodium cycling across the plasma membrane. The effect of methylprednisolone is similar indicating corresponding cellular mechanisms. However, unlike methylprednisolone, tirilazad produced no significant effect on calcium cycling across the plasma membrane. PNU-101033E in our test system caused cytotoxic effects on PBMC that did not allow us to quantify cellular actions on energy metabolism. Our results underline the view that tirilazad, first, is mimicking the high-dose immunosuppressive pharmacology of glucocorticoids such as methylprednisolone and, second, is likely to produce its therapeutic effects by direct physicochemical interactions with cellular membranes.