Effects of Indomethacin on Cyclic Nucleotide Levels and Histamine Release from Rat Serosal Mast Cells

Abstract

Previous studies in homogeneous and mixed cell systems on the changes in cyclic nucleotide levels that accompany the immunologic activation of mast cells for histamine release have not considered the extent to which these changes occur secondarily to the generation of the oxidative products of arachidonate. The recognition that mast cells themselves generate oxidative products of arachidonate upon immunologic activation and that exogenous prostaglandins can modulate cellular levels of 3′,5′-cyclic adenosine monophosphate (cyclic AMP) prompted the assessment of the effects of endogenous oxidation of arachidonate on changes in cyclic nucleotide levels accompanying immunologic activation. Thus, immunologic activation of purified rat serosal mast cells was carried out in the presence of a concentration of indomethacin that completely suppressed the oxidative conversion of arachidonate to the prostaglandins D₂ (PGD₂) and F_2a (PGF_2a) without having any effect on the time course and magnitude of histamine release. The immunologic activation of rat mast cells gave an early and a late monophasic rise of both cyclic AMP and 3′,5′-cyclic guanosine monophosphate (cyclic GMP). The inhibition of cyclo-oxygenase by 10 µM indomethacin abolished both monophasic rises in cyclic GMP and the second monophasic rise in cyclic AMP, but had no significant effect on the early peak of cyclic AMP that followed immunologic activation. Thus, those changes in cyclic nucleotide levels that are suppressed by indomethacin are not part of the primary activation-secretion event of mast cells and may be secondary to the generation of oxidative products of arachidonate. In contrast, the indomethacin-resistant elevations in cyclic AMP observed in the homogeneous rat mast cell system 5 to 15 sec after activation may represent an early event in the coupled activation-secretion response.