A possible mechanism of the inhibitory effect of endotoxin on adenylate cyclase.

The possible mechanism of the inhibitory effect of endotoxin on adenylate cyclase was investigated. Plasma membranes were isolated from porcine thyroid gland and rat liver. The effects of endotoxin on adenylate cyclase activity was determined. The adenylate cyclase activity followed in the presence of various concentrations of guanosine-imidodiphosphate (5 x 10(-8)-10(-6) M) and NaF (0.1-10 mM) was markedly inhibited by endotoxin. Moreover, the basal activity of adenylate cyclase was inhibited similarly. The inhibition was concentration dependent. At 400 micrograms/ml of endotoxin a 60% inhibition of adenylate cyclase both without and in the presence of activators was detected. The inhibitory effects of endotoxin and its radiodetoxified derivative were similar. Neither of the two investigated endotoxin preparations tested had any effect on the 3H-guanosine-imidodiphosphate binding activity of adenylate cyclase (neither on the binding capacity, nor on the Kd value). Forskolin activated adenylate cyclase was also inhibited markedly by both endotoxin and radiodetoxified endotoxin. These results suggest that beyond the other membrane effects there is a probability of direct inhibitory effect of endotoxin on the catalytic subunit of adenylate cyclase.