The effects of L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide) have been studied on pulmonary and other smooth muscle preparations in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-641,933 produced significant shifts in the dose-response curves to the prostaglandin endoperoxide analogues, U-44069 (pA2 7.06) and U-46619 (pA2 7.14), and prostaglandin (PG) F2 alpha (pA2 6.33) had minimal activity against contractions induced by histamine (pA2 4.38), 5-hydroxytryptamine (pA2 4.63), and acetylcholine (pA2 4.56) and slightly enhanced relaxation induced by PGE2. When tested on the guinea-pig gall bladder strip in vitro, L-641,953 antagonized contractions induced by U-44069 (pA2 7.03) but was less active against those induced by PGF2 alpha (pA2 6.03), PGE1 (pA2 5.62), and histamine (pA2 4.84). When tested in vitro on the guinea-pig pulmonary artery, L-651-953 significantly antagonized contractions induced by U-44069 (pA2 7.04), U-46619 (pA2 7.14), and PGF2 alpha (pA2 7.16) but was less effective against contractions induced by histamine (pA2 4.19). Schild analysis indicated that L-641,953 was fully competitive against contractions of either the guinea-pig tracheal chain induced by U-46619 or the guinea-pig pulmonary artery induced by U-44069 and U-46619. When tested on human platelets in vitro L-641,953 inhibited aggregation induced by U-44069 (IC50 1.3 X 10(-6) M) but not ADP.(ABSTRACT TRUNCATED AT 250 WORDS)

The actions of leukotrienes (LT's) C4, D4, E4 and F4 have been investigated in the perfused hind-limb of the anesthetized pig. In the blood perfused hind limb LTC4, D4 and E4 increased the perfusion pressure in a dose-dependent fashion whereas LTF4 decreased perfusion pressure. In the Tyrode perfused hind limb all LT's increased perfusion pressure (rank order potency LTC4 = LTD4 much greater than LTF4). The actions of LTF4 were not affected by a wide variety of pharmacological treatments, including indomethacin, methysergide and FPL-55712. The LT's aggregated porcine platelets (rank order potency LTC4 greater than LTF4 greater than LTD4) and induced the release of a platelet-derived vasodilatory mediator. The results provide pharmacological evidence of specific leukotriene receptors in vivo and that leukotrienes can independently modulate blood flow. These data suggest that important interactions may occur between platelets, the arachidonate lipoxygenase products and platelet-derived substances in response to inflammatory stimuli in the cardiovascular system.

The effects of L-640,035 (3-hydroxymethyl-dibenzo [b,f] thiepin-5,5-dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-640,035 produced significant shifts in the dose-response curves to a prostaglandin (PG) endoperoxide analogue (U-44069) (pA2 7.0), PGF2 alpha (pA2 5.9) and PGD2 (pA2 6.5). L-640,035 produced no significant shift in the dose-response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose-response curve to 5-hydroxytryptamine (5-HT) (pA2 5.2). With the exception of PGF2 alpha, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L-640,035, L-636,499, also produced significant parallel shifts in the dose-response curves to U-44069 (pA2 6.0) and PGF2 alpha (pA2 6.0), but with some reduction in the maximal contraction. When L-640,035 was administered intravenously to guinea-pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U-44069 (ED50 0.16 mg kg-1), leukotriene D4 (ED50 0.25 mg kg-1) and 5-HT (ED50 3.4 mg kg-1) but not histamine (ED50 greater than 10 mg kg-1) was observed. When L-640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U-44069 (ED50 0.85 mg kg-1) but not histamine (ED50 greater than 30 mg kg-1) was observed. 5 When L-640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg- significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mgkg1 i.v.) was observed with a duration of action of > 255 min. 6 It is concluded that L-640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.

In the presence of indomethacin, Leukotriene C4 (LTC4), LTD4 and LTE4 were shown to be contractile agents in vivo on guinea pig gall bladder strips. The respective pD2 values for LTC4, LTD4 ad LTE4 were 9.1, 9.1 and 7.7. The contractile effects of LTD4 were not mediated through the generation of cyclooxygenase products and were antagonized by the SRS-A antagonist FPL-55712. The effects of PGE1, PGF2α, the endoperoxide analogue U44069 and histamine on gall bladder strips were also examined. All these agents caused dose-related contractions but were considerably less potent than the leukotrienes. Leukotrienes are therefore potent contractile agents on the guinea pig gall bladder and may contribute to gall bladder contractions or spasms in vivo.