The mechanisms underlying the biphasic response (BR) of the circular muscle of the guinea pig ileum (CMGPI) to bradykinin (BK) have been examined. Both BK and lysyl-BK (1 nM to 1 microM) caused graded contractions followed by relaxations of the CMGPI, yielding EC50 of 21 and 92 nM for contraction and of 10 and 27 nM for relaxation, respectively. The selective B1 receptor agonist Des-Arg9-BK was without effect up to 3 microM. The potencies of BK and lysyl-BK to evoke BR were markedly increased by enalapril (3 microM) and decreased by raising the preparation tone with the thromboxane A2/prostaglandin H2-mimetic U46619 (30 ng/ml). The BR of CMGPI to BK was unaffected by atropine, yohimbine, pyrilamine, propranolol, prazosin, phorbol ester, des-Arg9-[leu8]-BK (1 microM, each), tetrodotoxin (0.3 microM), [3,4,5-trimethoxybenzoic acid-8-(diethylamino) octyl ester (10 microM), [N-6-(aminohexyl)-5-chloro-1-naphthalenosulfonamide (10 microM), glibenclamide (0.3 microM), nordihydroguaiaretic acid (50 microM), phenidone (30 microM) or dexamethasone (0.1 microM). However, indomethacin (3 microM), ibuprofen (30 microM) and 3-amino, 1-(m-[trifluoromethyl] phenyl)2-pyrazoline (10 microM) each abolished the relaxant and increased the contractile response to BK, suggesting that a cyclo-oxygenase-derived eicosanoid mediates relaxation and limits contraction. Prostaglandin (PG) E2 (up to 100 nM) caused only graded relaxations, PGF2 alpha (up to 3 microM) and 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (up to 300 ng/ml) caused only contractions and the PGI2 analog iloprost was without effect up to 1 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)