In the presence of the neutral metalloendopeptidase inhibitor, phosphoramidon, substance P (SP) is a highly potent spasmogen for isolated lung parenchymal strips as well as tracheal rings from the guinea pig. We studied the mechanism of action of this peptide, and of the related tachykinin, substance K (SK), on both tissue preparations. The cyclooxygenase inhibitors, indomethacin (1 microM) or aspirin (100 microM), in combination with phosphoramidon (1 microM) effectively block SP-induced contractions in lung parenchymal strips. The lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), the H1 antihistamine, pyrilamine (1 microM) and the anticholinergic agent, atropine (1 microM), all had no significant effect on SP-induced contractions. No detectable levels of thromboxane B2, or prostaglandins D2, E2, F2 alpha, or 6-keto-F1 alpha were released into the tissue bathing fluid. These data suggest that the contractile response of guinea pig lung parenchymal strips is mediated by cyclooxygenase metabolites, which are not released in significant concentration from the cells. In the presence of phosphoramidon, SK has a concentration-response curve similar to SP on guinea pig lung parenchymal strips. Its contractile activity is also inhibited by indomethacin but less effectively than SP. In marked contrast, the contractile responses of guinea pig tracheal tissues to the tachykinins were not affected significantly by indomethacin, alone or in combination with phosphoramidon. Additionally, tracheal tissue is 20- to 100-fold more sensitive to SK than SP in the presence or absence, respectively, of the endopeptidase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)