1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats.

There are conflicting data regarding the role of nitric oxide (NO) produced by inducible NO synthase (iNOS) in the pathophysiology of traumatic brain injury (TBI). In this report, we evaluated the effect of a potent selective (iNOS) inhibitor, 1400W, on histopathological outcome following TBI in a rat model of lateral fluid percussion brain injury. First, to design an appropriate treatment protocol, the parallel time courses of iNOS and neuronal NOS (nNOS) gene expression, protein synthesis, and activity were investigated. Early induction of iNOS gene was observed in the cortex of injured rats, from 6 to 72 h with a peak at 24 h. Similarly, iNOS protein was detected from 24 to 72 h and de novo synthesized iNOS was functionally active, as measured by Ca2+-independent NOS activity. The kinetic studies of nNOS showed discrepancies, since nNOS gene expression and protein synthesis were constant in the cortex of injured rats from 24 to 72 h, while Ca2+-dependent constitutive NOS activity was markedly decreased at 24 h, persisting up to 72 h. Second, treatment with 1400W, started as a bolus of 20 mg kg-1 (s.c.) at 18 h post-TBI, followed by s.c.-infusion at a rate of 2.2 mg kg-1 h-1 between 18 and 72 h, reduced by 64% the brain lesion volume at 72 h. However, the same treatment paradigm initiated 24 h post-TBI did not have any effect. In conclusion, administration of a selective iNOS inhibitor, 1400W, even delayed by 18 h improves histopathological outcome supporting a detrimental role for iNOS induction after TBI.     

Antagonistic effect of KC-404, a new anti-asthmatic agent, on leukotriene D4-induced contractile responses in isolated guinea pig smooth muscles

The inhibitory effects of KC-404, a novel clinically available anti-asthmatic drug, on leukotriene(LT) D4-, LTC4-, histamine- and acetylcholine(ACh)-induced contractile responses in isolated guinea pig lung parenchymal, tracheal and ileal longitudinal strips were compared using an organ bath system. In lung parenchyma, KC-404 antagonized LTD4 in a competitive fashion, whereas it antagonized histamine noncompetitively. The pA2 value against LTD4 was 7.39. KC-404 hardly antagonized LTC4 and ACh. A ranked order of potency estimated from its minimum effective concentrations (MEC) was LTD4 greater than histamine greater than LTC4 greater than ACh. In trachea, KC-404 antagonized LTC4 and LTD4 in a competitive fashion, while it antagonized histamine noncompetitively. The pA2 values against LTC4 and LTD4 were 5.99 and 6.51, respectively. KC-404 hardly antagonized ACh. A ranked order of the potency estimated from MEC was LTD4 greater than LTC4 greater than histamine greater than ACh. The pA2 values of KC-404 against LTD4 in lung parenchyma and trachea were little or not altered, while its inhibitory effect on histamine-induced contraction in trachea was markedly diminished by the pretreatment of tissues with indomethacin. In ileum, KC-404 noncompetitively antagonized all of the agonists used. A ranked order of the potency estimated from pD2 values was LTD4 divided by LTC4 greater than histamine greater than ACh. These results suggest that KC-404 is a selective antagonist of LTD4 and that it might interact with LTD4 receptor in airway smooth muscles but not in ileum. Another possibility that the drug might interact with LTD4 specific excitation-contraction coupling mechanism was also discussed.     

Influence of platelet-activating factor on leukotriene D4-induced contractions of the guinea pig parenchymal strip

Platelet-activating factor (PAF) and sulphidopeptide leukotrienes, such as leukotriene D4 (LTD4), are potent constrictors that are probably released simultaneously in a variety of inflammatory respiratory events. The purpose of the present study was to determine whether LTD4-induced contractions of guinea pig parenchymal lung strips (GPPS) are modified in the presence of PAF. The contractile responses of isolated GPPS to cumulative doses of LTD4, acetylcholine, histamine, and potassium chloride in the presence of PAF (0.1 nM, 0.1 microM) were compared with parallel controls. There was no significant alteration of the response to acetylcholine and potassium chloride and the PAF-induced inhibition of the response to histamine, although significant, was not concentration dependent. In contrast, PAF in a concentration range from 0.1 nM to 1.0 microM caused a marked, concentration-dependent reduction of LTD4-induced contractions. Pretreatment with the PAF receptor antagonist, BN52021, prevented the attenuation of LTD4-induced contraction by PAF. The attenuation of LTD4-induced contraction by PAF was also prevented by pretreatment with indomethacin or with the thromboxane synthase inhibitor U63,557A, but not by pretreatment with the lipoxygenase inhibitors BW755c or nordihydroguaiaretic acid. Thus inhibition of LTD4-induced GPPS contraction by PAF is receptor dependent and probably secondary to thromboxane generation. The respiratory smooth muscle response to leukotrienes may be modified significantly by concomitant PAF release.     

Pranlukast protects leukotriene C4- and D4-induced epithelial cell impairment of the nasal mucosa in vitro

To investigate the effect of pranlukast on leukotriene- induced airway mucosal epithelial dysfunction, samples of human nasal mucosa obtained during surgery for facial trauma were exposed to leukotriene C4 and/or D4 and observed on a TV screen magnified x 2,500. Leukotriene C4- and D4-induced ciliary inhibition and delayed mucosal surface alterations appeared several hours later. Pranlukast prevented both the mucosal epithelial cell dysfunction and the delayed epithelial cell alteration.     

Different mechanisms between thromboxane A2- and leukotriene D4-induced nasal blockage in guinea pigs

Although thromboxane (TX)A2 is involved in allergic rhinitis, the mechanisms inducing nasal blockage have not been elucidated. We evaluated the roles of nasal mucosal vascular changes following intranasal instillation of the TXA2 analog U-46619 or leukotriene (LT)D4 to induce nasal blockage in a guinea pig model of allergic rhinitis. Both U-46619- and LTD4-induced nasal blockages in sensitized animals were swiftly and completely suppressed by a vasoconstrictor, naphazoline. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester relieved LTD4-induced nasal blockage, but not U-46619-induced nasal blockage. Although both agonists produced vasodilatation of nasal mucosa in vivo, LTD4 caused vasodilatation while U-46619 caused vasoconstriction in vitro. Both LTD4- and U-46619-induced nasal blockages in vivo should depend on vasodilatation of nasal mucosa. LTD4-induced nasal blockage is induced by direct vasodilatation via nitric oxide. In contrast, U-46619-induced nasal blockage may be associated with contraction of a certain vein that should exist at the exit of capacitance vessels, leading to congestion of the nasal mucosa.     

Identification of leukotriene D4 specific binding sites in the membrane preparation isolated from guinea pig lung

A radioligand binding assay has been established to study leukotriene specific binding sites in the guinea pig and rabbit tissues. Using high specific activity [3H]-leukotriene D4 [( 3H]-LTD4), in the presence or absence of unlabeled LTD4, the diastereoisomer of LTD4 (5R,6S-LTD4), leukotriene E4 (LTE4) and the end-organ antagonist, FPL 55712, we have identified specific binding sites for [3H]-LTD4 in the crude membrane fraction isolated from guinea pig lung. The time required for [3H]-LTD4 binding to reach equilibrium was approximately 20 to 25 min at 37 degrees C in the presence of 10 mM Tris-HCl buffer (pH 7.5) containing 150 mM NaCl. The binding of [3H]-LTD4 to the specific sites was saturable, reversible and stereospecific. The maximal number of binding sites (Bmax), derived from Scatchard analysis, was approximately 320 +/- 200 fmol per mg of crude membrane protein. The dissociation constants, derived from kinetic and saturation analyses, were 9.7 nM and 5 +/- 4 nM, respectively. The specific binding sites could not be detected in the crude membrane fraction prepared from guinea pig ileum, brain and liver, or rabbit lung, trachea, ileum and uterus. In radioligand competition experiments, LTD4, FPL 55712 and 5R,6S-LTD4 competed with [3H]-LTD4. The metabolic inhibitors of arachidonic acid and SKF 88046, an antagonist of the indirectly-mediated actions of LTD4, did not significantly compete with [3H]-LTD4 at the specific binding sites. These correlations indicated that these specific binding sites may be the putative leukotriene receptors in the guinea-pig lung.     

Study of mechanisms mediating contraction to leukotriene C4, D4 and other bronchoconstrictors on guinea pig trachea

Contractions of guinea pig trachea in the absence and presence of indomethacin to LTD4 greater than LTC4 greater than K+ greater than histamine greater than acetylcholine were reduced following a 45 minute exposure of the tissues to calcium-free Krebs' solution (Ca2+-free Krebs' solution), were further reduced by a transient exposure to EGTA (1.25 mM) in Ca2+-free Krebs' solution and were virtually abolished when tested in the presence of EGTA (0.125 mM) in Ca2+-free Krebs' solution. In normal Krebs' solution (2.5 mM Ca2+) the Ca2+ entry blockers nifedipine (N) much greater than D-600 greater than verapamil (V) greater than diltiazem (D) almost completely abolished the contractions to K+ but blocked only a component of the maximum response to the other agonists. After exposure to Ca2+-free Krebs' solution for 45 minutes, any residual contractions to LTC4 & LTD4, were reversed by low concentrations of N (0.3 microM) or D-600 (2.1 microM). Leukotrienes appear to mobilize a superficial and a bound store of Ca2+ which gains entry through at least two types of Ca2+ channels (or mechanisms), one of which is blocked by N and D600. K+-induced contractions appear to be dependent on superficial and tightly bound Ca2+ but entry is solely through channels which are blocked by the Ca2+ entry blockers studied. Contraction to histamine and acetylcholine persisted following exposure of the tissues to Ca2+ free Krebs' solution but contractile activity was virtually abolished in Ca2+ free Krebs' solution containing EGTA. Residual contractions to histamine and part of the residual contractions to acetylcholine in Ca2+-free Krebs' solution were blocked by low dose N (0.3 microM) or D600 (2.1 microM). These findings suggest a major role for extracellular Ca2+ during spasmogen-induced contraction in this tissue.     

Comparative effects of platelet activating factor, leukotriene D4 and histamine on guinea pig trachea, bronchus and lung parenchyma

The myotropic effect of platelet activating factor (PAF), leukotriene D4 (LTD4) and histamine were compared on guinea pig pulmonary tissues. The initial administration of PAF induced a contraction of strips of trachea, bronchus and lung parenchyma. However subsequent injections were characterized by relaxation of trachea and bronchus and a highly reduced (if any) contraction of the parenchyma. The three tissues of the guinea pig respiratory system contracted strongly to leukotriene D4 and histamine. Indomethacin blocked PAF-induced relaxation of the trachea and bronchus and reduced the contraction of the lung parenchyma. The injection of PAF in the pulmonary circulation stimulated the release of substance(s) causing the contraction of the trachea, bronchus and parenchyma. This study suggests that PAF is not a direct agonist of bronchoconstriction.     

Cilastatin (MK 0791) is a potent and specific inhibitor of the renal leukotriene D4-dipeptidase

The metabolism of leukotriene D4 to leukotriene E4 by a dipeptidase of kidney tissue is strongly inhibited by cilastatin (MK 0791) a known renal dehydropeptidase-I inhibitor. The comparison with similar enzyme activities from other tissues (liver, lung, serum, polymorphonuclear granulocytes) revealed a high specificity of cilastatin for the kidney enzyme which was found to be associated with the microsomal fraction. The lowest detectable inhibitory concentration of cilastatin within renal tissue was 8 X 10(-8)M.     

Inhibitory effects of a lipoxygenase inhibitor nordihydroguaiaretic acid on antagonism of leukotriene C4-induced contractions of isolated guinea-pig trachea

We have studied the effects of a lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) on antagonism of leukotriene (LT) C4-induced contractions of isolated guinea-pig trachea and the results were compared to that of a cyclooxygenase inhibitor indomethacin. NDGA (30 microM) as well as indomethacin (5 microM) inhibited LTC4-induced contractions. But, in the presence of indomethacin NDGA was ineffective to inhibit the LTC4 response, whereas two other lipoxygenase inhibitors, phenidone (3-30 microM) and 5,8,11,14-eicosatetraynoic acid (ETYA, 10 microM), markedly inhibited it. The antagonist action of an LTD4 receptor antagonist FPL55712 against LTC4-induced contractions was significantly reduced by NDGA (10-30 microM), but indomethacin had no effect on it. NDGA possessed the same inhibitory effect on the LTC4 antagonism in the presence of indomethacin, but 0.3 microM phenidone and 1 microM ETYA which did not inhibit the LTC4 response had no effect on it. NDGA also inhibited the relaxant response of isoproterenol on the contraction elicited by 30 nM LTC4, but did not affect those of forskolin and aminophylline. The relaxant response of isoproterenol on the LTC4 response was not inhibited by indomethacin, 0.3 microM phenidone and 1 microM ETYA. In the presence of a gamma-glutamyltranspeptidase inhibitor, L-serine borate (SB, 45 mM), NDGA had no effect on the LTC4 antagonism and the relaxant response of isoproterenol. In contrast, NDGA significantly inhibited the relaxant response of isoproterenol on 30 microM histamine- and 30 microM acetylcholine-induced contractions, but it did not affect the histamine antagonism by a histamine H1-blocker pyrilamine. These results suggest that some putative non-prostanoids are involved in LTC4-induced contractions of guinea-pig trachea and which regulate the effects of LTD4 antagonism and beta-adrenoceptor activation.     

3-Hydroxy-4-methyl-5-pentyl-2-iminopyrrolidine: a potent and highly selective inducible nitric oxide synthase inhibitor

(3S,4S,5R)-2-Imino-4-methyl-5-pentyl-3-pyrrolidinol hydrochloride (1) is a potent inducible nitric oxide synthase (i-NOS) inhibitor that has three times the selectivity of its parent, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine hydrochloride (2).     

Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist

L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.     

Effects of timolol, indomethacin, and MK-571 on bronchoconstriction to infused leukotriene D4 in guinea pigs

Continuous intravenous infusions of leukotriene D4 produced a prolonged but variable bronchoconstriction (approximately a 200% increase in lung resistance (RL) and a 50% decrease in dynamic compliance (Cdyn] in anesthetized and paralysed guinea pigs that peaked within 1-1.5 min and was followed by a somewhat smaller secondary plateau response. The overall response was delayed (time to peaks) but not significantly reduced by pretreatment with the cyclooxygenase inhibitor indomethacin (1 mg/kg), was markedly potentiated by the beta-adrenoceptor antagonist timolol (5 micrograms/kg), and was partially and completely blocked by pretreatment with 0.1 and 1.0 mg/kg, respectively, of the leukotriene D4 receptor antagonist MK-571. MK-571 prevented the response in indomethacin-treated guinea pigs but was considerably more active at preventing and reversing the potentiated responses (lower dose of leukotriene D4) in animals treated with indomethacin and timolol. Additional studies in indomethacin- and timolol-treated animals demonstrated that MK-571 was active with good duration of action by the aerosol route of administration (30 min and 4 h pretreatment). The technique of infusing leukotrienes into untreated, indomethacin-treated, and indomethacin- and timolol-treated guinea pigs is a useful method to study the action and interaction of leukotriene receptor antagonists.     

Effects of platelet-activating factor, thromboxane A2 and leukotriene D4 on isolated perfused rat liver

Vasoconstrictive lipid mediators, thromboxane A(2) (TxA(2)), platelet-activating factor (PAF) and leukotriene D(4) (LTD(4)) have been implicated as mediators of liver diseases. There are species differences in the primary site of hepatic vasoconstriction in response to these mediators. We determined the effects of a TxA(2) analogue (U-46619), PAF and LTD(4) on the vascular resistance distribution, weight and oxygen consumption of isolated rat livers portally perfused with blood. The sinusoidal pressure was measured by the double occlusion pressure (P(do)), and was used to determine the pre- (R(pre)) and post-sinusoidal (R(post)) resistances. All these three mediators increased the hepatic total vascular resistance (R(t)). The responsiveness to PAF was 100 times greater than that to U-46619 or LTD(4). Both of PAF and U-46619 predominantly increased R(pre) over R(post). At the comparable increased R(t) levels, U-46619 more preferentially increased R(pre) than PAF. In contrast, LTD(4) increased both the R(pre) and R(post) to similar extent. U-46619 caused liver weight loss, while high concentrations of either LTD(4) or PAF produced liver weight gain, which was caused by substantial post-sinusoidal constriction and increased P(do). PAF and U-46619 decreased hepatic oxygen consumption while LTD(4) induced biphasic change of an initial transient decrease followed by an increase. In conclusion, PAF is the most potent vasoconstrictor of rat hepatic vessels among these three mediators. Both TxA(2) and PAF constrict the pre-sinusoidal veins predominantly. TxA(2) more preferentially constricts the pre-sinusoids than PAF, resulting in liver weight loss. However LTD(4) constricts both the pre- and post-sinusoidal veins similarly. High concentrations of LTD(4) and PAF cause liver weight gain by substantial post-sinusoidal constriction. PAF and TxA(2) decrease hepatic oxygen consumption, whereas LTD(4) causes a biphasic change of it.     

Generation of leukotriene C4, leukotriene B4, and prostaglandin D2 by immunologically activated rat intestinal mucosa mast cells

Mucosal mast cells (MMC) were isolated from the intestine of Nippostrongylus brasiliensis-infected rats and then activated with Ag or with anti-IgE in order to assess their metabolism of arachidonic acid to leukotriene (LT) C4, LTB4, and prostaglandin D2 (PGD2). After challenge of MMC preparations of 19 +/- 1% purity with five worm equivalents of N. brasiliensis Ag, the net formation of immunoreactive equivalents of LTC4, LTB4, and PGD2 was 58 +/- 8.3, 22 +/- 4.5, and 22 +/- 3.4 ng/10(6) mast cells, respectively (mean +/- SE, n = 7). When MMC preparations of 56 +/- 9% purity were activated by Ag, the net generation of immunoreactive equivalents of LTC4, LTB4, and PGD2/10(6) MMC was 107 +/- 15, 17 +/- 5.4, and 35 +/- 18 ng, respectively. These data indicate that the three eicosanoids originated from the MMC rather than from a contaminating cell. Analysis by reverse phase HPLC of the C-6 sulfidopeptide leukotrienes present in the supernatants of the activated MMC preparations of lower purity revealed LTC4, LTD4, and LTE4. In a higher purity MMC preparation only LTC4 was present, suggesting that other cell types in the mucosa are able to metabolize LTC4 to LTD4 and LTE4. The release of histamine and the generation of eicosanoids from intestinal MMC and from peritoneal cavity-derived connective tissue-type mast cells (CTMC) isolated from the same N. brasiliensis-infected rats were compared. When challenged with anti-IgE, these MMC released 165 +/- 41 ng of histamine/10(6) mast cells, and generated 29 +/- 3.6, 12 +/- 4.2, and 4.7 +/- 1.0 ng (mean +/- SE, n = 3) of immunoreactive equivalents of LTC4, LTB4, and PGD2/10(6) mast cells, respectively. In contrast, CTMC isolated from the same animals and activated with the same dose of anti-IgE released approximately 35 times more histamine (5700 +/- 650 ng/10(6) CTMC), generated 7.5 +/- 2.3 ng of PGD2/10(6) mast cells, and failed to release LTC4 or LTB4. These studies establish, that upon immunologic activation, rat MMC and CTMC differ in their quantitative release of histamine and in their metabolism of arachidonic acid to LTC4 and LTB4.     

Optical isomers of a leukotriene B4 antagonist have differential effects on granulocyte diapedesis in the guinea pig dermis.

Leukotriene B4 (LTB4) is a proinflammatory product of arachidonic acid metabolism that has been implicated in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB4 has been shown to elicit a dose-dependent infiltration of granulocytes as assessed by the level of the neutrophil marker enzyme myeloperoxidase. SC-41930 [7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid] is a potent LTB4 receptor antagonist. When compounds were coadministered along with LTB4 (35 ng) into the dermal site, racemic SC-41930, (+)-SC-41930, and (-)-SC-41930 each inhibited granulocyte accumulation with ED50 values of 340 +/- 30, 98 +/- 5.7, and 1000 +/- 142 ng, respectively; when given intravenously inhibited with ED50 values of 0.5 +/- 0.06, 0.3 +/- 0.04, and 1.4 +/- 0.19 mg/kg, respectively; and when given intragastrically inhibited with ED50 values of 1.7 +/- 0.20, 1.4 +/- 0.23, and 3.0 +/- 0.41 mg/kg, respectively.     

Effects of a 48 hour continuous intravenous infusion of CGS 13080-primagrel, a selective thromboxane synthetase inhibitor, on the perinatal and early postnatal period in the guinea pig.

CGS 13080, imidazo[1,5-a]pyridine-5-hexanoic acid, was evaluated for perinatal and postnatal effects in third trimester pregnant guinea pigs and their offspring. The compound was administered via 48 hour continuous intravenous infusion to a group of pregnant guinea pigs (n = 16) at a dose of 3 mg/kg/hr starting on gestational day 52 (via chronically implanted indwelling jugular venous cannulas). A saline control group (n = 12) received equivalent volumes of normal saline 0.5 ml/kg/hr throughout the dosing period. A third group (surgery-sham, n = 16) was subjected to cannulation but not infused. A gross examination of each dam and piglets was conducted at necropsy on day 5 of lactation. The neonatal brains and all gross lesions (maternal and neonatal) were removed and fixed for histopathological examination. Compound-related clinical signs were noted in dams during the dosing phase of gestation. Six guinea pigs developed cephalic lymphatic swelling during the infusion. This observation may be correlated to the reported redistribution of fluid volume to the thorax of guinea pigs given intravenous injections of CGS 13080. There were no compound-induced effects on labor, delivery, or any of the examined reproductive parameters. There were no compound-related clinical signs, or effects on survival, body weight and developmental parameters in the F1 generation. Histopathological examination of the brains and other organs did not reveal any compound-related abnormalities. Based on these results, it was concluded that CGS 13080 did not elicit adverse perinatal and postnatal effects in guinea pigs.     

15-Acetylthioxy-furodysinin lactone, isolated from a marine sponge Dysidea, sp. is a potent agonist to human leukotriene B4 receptor

A sesquiterpene thioacetate, 15-acetylthioxy-furodysinin (SK&F 105900) has been isolated from the sponge Dysidea SP. This compound can bind specifically to the human peripheral blood polymorphonuclear leukocyte (PMN) and to the differentiated human monocytic leukemic U-937 cell membrane leukotriene B4 (LTB4) receptors with high-affinity. This compound can also promote a concentration-dependent chemotaxis in PMNs and an intracellular calcium mobilization in U-937 cells that can be blocked by the LTB4 receptor antagonist, LY-223982. Furthermore, the calcium mobilization induced by SK&F 105900 can specifically cross-desensitize with the LTB4-induced calcium mobilization. These observations indicate that SK&F 105900 is a novel and specific high-affinity agonist that can bind to the LTB4 receptors and activate the receptor-mediated signal transduction processes in human PMN and U-937 cells.