On the mechanism by which theophylline inhibits histamine release from rat mast cells

Theophylline (2.5 mM) did not influence the spontaneous release of histamine but inhibited histamine release induced by antigen, compound 48/80 or phosphatidylserine. The effect on 48/80-induced histamine release could not be reversed by increasing extracellular Ca2+. Exogenous adenosine (10(-8) to 10(-4) M) did not influence spontaneous histamine release or 48/80-induced release but potentiated antigen-induced release. The adenosine potentiation was competitively inhibited by theophylline in concentrations (10(-5) to 10(-4) M) lower than those required to inhibit antigen-induced histamine release in the absence of adenosine. In order to see if endogenous adenosine levels are high enough to potentiate an anaphylactic histamine release in vivo, adenosine was determined in mast cell incubates and in plasma from 4 different strains of rat. The levels were 0.18 to 0.99 microM in plasma, which is sufficient to cause significant potentiation of histamine release, but only 3 x 10(-8) M in mast cell incubates. Theophylline (2.5 mM) increased cAMP levels about 100%, whereas adenosine (10(-5) M) had little effect on cAMP and cGMP levels. However, when incubated together, adenosine could inhibit the theophylline-induced increase in cAMP levels but not the inhibition of histamine release. It is concluded that the effect of low concentrations of theophylline could be due partly to antagonism of adenosine effects. In addition, in higher doses, theophylline appears to exert an inhibitory action that is unrelated to cyclic nucleotides, extracellular calcium and adenosine.