DEFECT IN POTENTIATION OF ADENYLYL-CYCLASE CORRELATES WITH BRONCHIAL HYPERREACTIVITY

Background: Adenylyl cyclase is a transmembrane signaling system invol ved in the inhibition of cellular responses. Recently, we showed that the activity of adenylyl cyclase may be potentiated by stimuli that in duce an increase of cellular responses but that do not activate adenyl yl cyclase. This is probably an important physiologic feedback mechani sm that prevents cells from becoming ''overstimulated.'' Objective: Be cause increased cellular activities are frequently observed in persons with asthma, we hypothesized that a defect in potentiation of adenyly l cyclase might be involved. Methods: Potentiation of isoprenaline-ind uced adenosine cyclic monophosphate (cAMP) production with the mitogen phytohemagglutinin (PHA; 45 mu g/ml) or the calcium ionophore A23187 (1 mu mol/L) was studied in peripheral blood mononuclear cells taken f rom patients with asthma (n = 8) and healthy control subjects (n = 11) . Results: Isoprenaline-induced cAMP production was potentiated signif icantly in the healthy control subjects (PHA, 110% +/- 15%; A23187, 92 % +/- 25%). In contrast, potentiation was not seen with PHA ol A23187 in the total group of patients with asthma. However; some patients sho wed weak potentiation, whereas in others PHA decreased isoprenaline-in duced CAMP production. Moreover, the effect of PHA isoprenaline-induce d cAMP production correlated significantly with the degree of bronchia l hyperreactivity in patients with asthma (r = 0.96; p = 0.0001). Conc lusions: The observed defect in signal transduction could play an impo rtant part in bronchial hyperresponsiveness.