The ability of endothelin-1 (ET-1) to modulate the cyclic nucleotides, guanosine 3' 5' cyclic monophosphate (cyclic GMP) and adenosine 3' 5' cyclic monophosphate (cyclic AMP) was assessed in the main elastic pulmonary elastic artery (4 - 5 mm i.d.) and the small muscular pulmonary arteries (150 - 200 micrometer i.d.) of the rat. ET-1 caused an increase in cyclic GMP in the larger vessels but had no effect in the smaller arteries. The increase in cyclic GMP was not dependent on an intact endothelium and was inhibited by the ET(A)-receptor antagonist FR139137 (1 microM). ET-1 caused a decrease in cyclic AMP in the main pulmonary arteries, an effect that was partially blocked by FR139317 but not influenced by the ET(B)-receptor antagonist BQ-788 (1 microM) or removal of the vascular endothelium. In contrast, ET-1 caused an increase in cyclic AMP in the small vessels, an effect that was blocked by BQ-788 but unaffected by FR139317. In the main pulmonary arteries, ET-1 caused enhanced incorporation of radiolabelled ADP-ribose by cholera toxin into G(i)2 in the main pulmonary artery, an indicator of its receptor-mediated activation. In summary, we have shown that in the small muscular pulmonary artery of the rat, (where ET(B) mediated vasoconstriction prevails), there is an ET(B)-mediated increase in cyclic AMP with no net effect on cyclic GMP levels. In the large arteries, (where vasoconstriction is mediated via the ET(A) receptor), there is an ET(A)-mediated increase in cyclic GMP (endothelium independent) and an ET(A)-mediated (endothelium independent) decrease in cyclic AMP.