ENDOTHELINS (ETs) elicit a diversity of cellular responses in cultured astrocytes that suggest an important role of these peptides in glial cell function. Stimulation of astroglial ET receptors induces phosphoinositide (PI) hydrolysis and intracellular calcium mobilization, but little is known about the signalling events that occur downstream of this system. Here we show that in rat cerebellar astroglia in culture ETs produce a receptor-mediated stimulation of cyclic GMP (cGMP) formation that is rapid and totally dependent on nitric oxide synthase (NOS) activity. The effect is blocked by an inhibitor of PI phospholipase C, compound U73122, and by depletion of intracellular calcium stores with thapsygargin. These results indicate that calcium released by inositol trisphosphate is responsible for NOS activation and subsequent cGMP formation.