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Biomedical subjects

J H Fleisch

Publications and source records attributed to J H Fleisch.

At least 19 recordsLinked to original sources
PubMed2002

Inhibition of antigen-induced arthritis in guinea pigs by a selective LTB4 receptor antagonist LY293111Na.

OBJECTIVE AND DESIGN: To investigate the role of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in the development and progression of antigen-induced arthritis (AIA) in guinea pigs and rats. METHODS: Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) into the knee joint of immunized guinea pigs or rats. The effect of a potent and selective LTB4 receptor antagonist, LY29311INa (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]-phenoxy]benzoic acid sodium salt) was compared with those of indomethacin and dexamethasone. The effect of LY293111Na on adjuvant arthritis in rats was also examined. RESULTS: LY293 111Na (5 to 50 mg/kg b.i.d.) significantly inhibited knee joint swelling and histopathological changes of AIA in guinea pigs, but not in rats. Especially its protective effect against bone and cartilage destruction was substantial. In contrast, the cyclooxygenase inhibitor indomethacin significantly inhibited AIA in rats, but slightly inhibited in guinea pigs, while dexamethasone markedly inhibited AIA in both guinea pigs and rats. Increases of LTB4 and myeloperoxidase (MPO) activity were observed in the knee joint tissue of AIA guinea pigs, and LY293111Na dose-dependently inhibited the increase of MPO activity. Moreover, in adjuvant arthritic rats, LY293111Na showed slight inhibitory effect, while indomethacin showed marked inhibition. CONCLUSIONS: LTB4 but not PGE2 appeared to play important roles as an effective mediator in joint, particularly in cartilage and bone destruction of AIA in guinea pigs probably by inducing polymorphonuclear leukocytes (PMNs) chemotaxis to the joint tissue. In contrast, PGE2 but not LTB4 is an important mediator of arthritis in rats.

Animals↗
PubMed2001

LY393615, a novel neuronal Ca(2+) and Na(+) channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia.

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.

Animals↗
PubMed2001

Effects of leukotriene B4 receptor antagonist, LY293111Na, on antigen-induced bronchial hyperresponsiveness and leukocyte infiltration in sensitized guinea pigs.

OBJECTIVE AND DESIGN: LY29311 Na, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy] propoxy] -phenoxy]-benzoic acid sodium salt, is a novel leukotriene B4 (LTB4) receptor antagonist. Its effects on guinea pig models of asthma were compared with those of dexamethasone. METHODS: Effects of LY293111Na were tested in antigen (ovalbumin, OA)-induced bronchial hyperresponsiveness (BHR) and leukocyte accumulation in actively sensitized guinea pigs. Its effects on antigen-induced acute bronchoconstriction in passively sensitized guinea pigs were also studied. RESULTS: LY293111 Na (10 to 30 mg/kg p.o., 1 h before and 6 h after OA challenge) inhibited BHR to acetylcholine. LY293111 Na (3 mg/kg p. o.) significantly inhibited accumulation of neutrophils in bronchoalveolar lavage (BAL) fluid 24 h after antigen challenge but it did not inhibit accumulation of eosinophils and macrophages at any doses used. In contrast, dexamethasone (30 mg/kg p.o., 4 h before OA challenge) not only inhibited BHR but also reduced the infiltration of all three types of leukocytes. A significant increase of LTB4 levels in BAL fluid was noted at 3 and 15 min after the antigen challenge. LY293111Na did not inhibit antigen-induced acute bronchoconstriction in passively sensitized guinea pigs. CONCLUSION: These results indicate that LTB4 may participate in antigen-induced BHR but not in eosinophil infiltration and acute bronchoconstriction in guinea pigs.

Acetylcholine↗
PubMed2000

Effects of the second-generation leukotriene B(4) receptor antagonist, LY293111Na, on leukocyte infiltration and collagen-induced arthritis in mice.

The effects of the second-generation leukotriene B(4) receptor (LTB(4) receptor) antagonist, 2-[2-propyl-3-¿3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxy-phenoxy]-propo xy¿phenoxy]benzoic acid sodium salt (LY293111Na), on leukotriene B(4)-induced leukocyte infiltration and interleukin-1-accelerated collagen-induced arthritis in mice were studied. Neutrophil infiltration induced into an air pouch by leukotriene B(4) was dose-dependently inhibited by LY293111Na and strongly so by another LTB(4) receptor antagonist, 4-[5-¿4-(aminoiminomethyl)phenoxy¿pentoxy]-3-methoxy-N, N-bis(1-methylethyl) (Z)-2butenedioate (1:1) (CGS25019C). Both compounds significantly inhibited the increase of the arthritis index and the ankle bone destruction in interleukin-1-accelerated collagen-induced arthritis. Phenidone, a 5-lipoxygenase inhibitor, also inhibited interleukin-1-accelerated collagen-induced arthritis, while indomethacin and tenidap, cyclooxygenase inhibitors, had slight inhibitory effects. Injection of interleukin-1 elicited a marked increase of the leukotriene B(4) level in arthritic paws, while the prostaglandin E(2) level was slightly increased. These findings indicate clearly that leukotriene B(4) is an important mediator of interleukin-1-accelerated collagen-induced arthritis in mice. If this can be extrapolated to man, LTB(4) receptor antagonists might be useful for treatment of the acute progressive phase of human arthritis.

Animals↗
PubMed2000

ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia.

In the present studies, we have evaluated the effects of N-[4-(2-¿[(3-Chlorophenyl)methyl]amino¿ethyl)phenyl]-2-thiophenecarbo ximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC(50) values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 microM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions.

Amidines↗
PubMed1999

Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI.

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA2 (sPLA2). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA2 activity with an IC50 of 9 +/- 1 nM or 7.3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 40-fold less active against human, group IB, pancreatic sPLA2 and was inactive against cytosolic PLA2 and the constitutive and inducible forms of cyclooxygenase. Human sPLA2-induced release of thromboxane A2 (TXA2) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC50 of 0.79 microM. The release of TXA2 from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA2-induced production of TXA2 with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA2 produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent KB of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA2 protein inhibited serum sPLA2 activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA2 inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA2 in various inflammatory disease states.

Acetates↗
PubMed1999

Pharmacologic actions of the second-generation leukotriene B4 receptor antagonist LY293111: in vitro studies.

The in vitro actions were investigated of LY293111, a potent and selective leukotriene B4 (LTB4) receptor antagonist, on human neutrophils, human blood fractions, guinea pig lung membranes, and guinea pig parenchymal and tracheal strips. The IC50 for inhibiting [3H]LTB4 binding to human neutrophils was 17.6 +/- 4.8 nM. LY293111 inhibited LTB4-induced human neutrophil aggregation (IC50 = 32 +/- 5 nM), luminol-dependent chemiluminescence (IC50 = 20 +/- 2 nM), chemotaxis (IC50 = 6.3 +/- 1.7 nM), and superoxide production by adherent cells (IC50 = 0.5 nM). Corresponding responses induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine were inhibited by 100-fold higher concentrations of LY293111. LTB4 binding to guinea pig tissues and subsequent activation were also inhibited. The Ki for inhibition of [3H]LTB4 binding to lung membranes was 7.1 +/- 0.8 nM; IC50 for preventing binding of [3H]LTB4 to spleen membranes was 65 nM. The compound inhibited LTB4-induced contraction of guinea pig lung parenchyma. At 10 nM, LY293111 caused a parallel rightward shift of the LTB4 concentration-response curve. At higher concentrations, plots were shifted in a nonparallel manner, and maximum responses were depressed. LY293111 did not prevent antigen-stimulated contraction of sensitized trachea strips. At micromolar concentrations, LY293111 inhibited production of LTB4 and thromboxane B2 by plasma-depleted human blood stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine and thrombin. In addition, at these higher concentrations, formation of LTB4 by A23187-activated whole blood and conversion of arachidonic acid to LTB4 by a human neutrophil cytosolic fraction were inhibited. In summary, LY293111 is a second-generation LTB4 receptor antagonist with much improved potency in a variety of functional assay systems.

Animals↗
PubMed1996

Recombinant human secretory phospholipase A2 released thromboxane from guinea pig bronchoalveolar lavage cells: in vitro and ex vivo evaluation of a novel secretory phospholipase A2 inhibitor.

The primary objective of this study was to develop a functional assay that could provide rapid and reliable information on some pharmacologic characteristics of a novel inhibitor of human secretory phospholipase A2 (sPLA2). Guinea pig bronchoalveolar lavage (BAL) fluid, containing predominantly macrophages, eosinophils and epithelial cells, released thromboxane A2, as measured by thromboxane B2, in a concentration-dependent manner on exposure to recombinant human sPLA2 (rh-sPLA2). Similarly, n-formyl-L-methionyl-L-leucyl-L-phenylalanine (n-F-Met-Leu-Phe) or arachidonic acid also released this lipid mediator. Indomethacin, a cyclooxygenase inhibitor, blocked synthesis of thromboxane in response to these agents. p-Bromophenacylbromide-inactivated rh-sPLA2 was substantially less effective than the untreated enzyme in causing release of thromboxane. LY311727 is a potent indole-derived inhibitor of the isolated enzyme (IC50 = 23 nM). Incubation of this agent with BAL cells, just before addition of rh-sPLA2, reduced release of thromboxane with an IC50 = 1.8 x 10(-6) M. Specificity for sPLA2 was demonstrated in that LY311727, unlike indomethacin, did not reduce synthesis and subsequent release of thromboxane A2 in response to arachidonic acid. Using this technique as a basis, we determined whether LY311727 could sufficiently accumulate in lung after i.v. administration to inhibit rh-sPLA2-induced thromboxane A2 release from BAL cells. The compound, given i.v. to guinea pigs 5 min before collecting BAL fluid, produced a dose-dependent inhibition of rh-sPLA2 with an ED50 = 50 mg/kg. Thus, new in vitro and ex vivo assays were developed that permit functional evaluation of novel sPLA2 inhibitors. These techniques should serve as secondary assays for evaluation of human sPLA2 inhibitory activity from a chemical series and in addition provide initial data related to metabolic stability and distribution to the lung.

Animals↗
PubMed1995

Synthetic and structure/activity studies on acid-substituted 2-arylphenols: discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]-propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist.

Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B4. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB4. A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2-[2-propyl-3-[3-[2-ethyl-4-(4- fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC50 = 17 +/- 4.6 nM) and guinea pig lung membranes (IC50 = 6.6 +/- 0.71 nM), inhibition of LTB4-induced expression of the CD11b/CD18 receptor on human neutrophils (IC50 = 3.3 +/- 0.81 nM), and inhibition of LTB4-induced contraction of guinea pig lung parenchyma (pKB = 8.7 +/- 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB4-induced airway obstruction in the guinea pig when dosed by the oral (ED50 = 0.40 mg/kg) or intravenous (ED50 = 0.014 mg/kg) routes. A specific LTB4 receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D4 (LTD4), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.

Airway Obstruction↗
PubMed1995

Differential relaxant responses of guinea-pig lung strips and bronchial rings to sodium nitroprusside: a mechanism independent of cGMP formation.

The biochemical mechanism subserving smooth muscle relaxant effects of sodium nitroprusside was examined on U46619, 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy PGF2 alpha, precontracted guinea-pig lung strips and hilar bronchial rings. Lung strips were resistant to the relaxant action of sodium nitroprusside or sodium nitrite (NaNO2), whereas they markedly relaxed to 8-bromo-cyclic GMP (8-Br-cGMP), a membrane permeable analogue of cGMP. Precontracted bronchial rings completely relaxed to sodium nitroprusside, NaNO2, or 8-Br-cGMP in a concentration-dependent manner. Sodium nitroprusside (10 microM) substantially raised tissue cGMP level in lung strips. Conversely, sodium nitroprusside had no detectable effect on cGMP levels in bronchial rings. In the presence of 10 microM dipyridamole, an agent which preferentially inhibits cGMP-specific phosphodiesterase, cGMP levels in lung strips treated with sodium nitroprusside was significantly enhanced, but sodium nitroprusside demonstrated no relaxant effect on the preparations. However, dipyridamole potentiated sodium nitroprusside-induced precontracted bronchial ring relaxation without affecting the bronchial tissue cGMP level. In the presence of 10 microM LY83583 (6-anilino-5,8-quinoline-dione), a specific cGMP concentration-lowering agent, sodium nitroprusside-mediated elevation of cGMP level in lung strips was significantly reduced with no effect on the functional response. LY83583 demonstrated no inhibitory effect on either relaxation or cGMP level in bronchial rings treated with sodium nitroprusside. Our results suggest that precontracted smooth muscle in lung strips and in hilar bronchi respond distinctly to sodium nitroprusside. Furthermore, sodium nitroprusside mediates bronchial smooth muscle relaxation by mechanisms unrelated to cGMP.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Contraction of guinea pig inferior vena cava by eicosanoids.

Guinea pig inferior vena cava contracted in response to leukotriene (LT)C4, LTD4, LTE4 U46619, phenylephrine, histamine, and KCl. Although LTC4, LTD4, and U46619 were the most potent agonists, active tension generated by these eicosanoids was only about half that of histamine or KCl. LTE4 and phenylephrine were marginally active. Biochemical analysis showed vena cava able to convert about 23% LTC4 to LTD4 and LTE4 in 45 min. Pretreatment with acivicin prevented this by abrogating conversion of LTC4 to LTD4. A subthreshold concentration of LTE4 reduced responses to LTC4 and LTD4. LY171883 and WY-48252 competitively antagonized LTD4-induced contractions of vena cava. In contrast, these antagonists blocked contractions to LTC4 in a biphasic manner. Lower segments of the LTC4 concentration-response curves were less affected than the upper portion suggesting the possibility of 2 LTC4 receptor subtypes. Our results indicate that LTE4 is a weak or partial agonist in this tissue and furthermore they suggest a lack of high affinity receptors for LTE4 favoring LTC4 and LTD4. Indomethacin did not influence contractions to the leukotrienes or histamine. However, the response to U46619 was greatly enhanced suggesting release of a vasodilator prostaglandin as part of the overall response of the vena cava to the thromboxane A2 mimetic.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

A novel leukotriene B4-receptor antagonist in endotoxin shock: a prospective, controlled trial in a porcine model.

OBJECTIVE: To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B4-receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin. DESIGN: Prospective, randomized, controlled trial. SETTING: Laboratory at a large university medical center. SUBJECTS: Twenty-five, immature, random-bred swine. INTERVENTIONS: Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 micrograms/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value. MEASUREMENTS AND MAIN RESULTS: Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration. CONCLUSIONS: These data suggest that leukotriene B4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB4 receptors.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist.

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.0, respectively. In the functional correlate of the binding studies, LY255283 competitively reduced contractile responses of lung parenchyma to LTB4 (pA2 = 7.2). LTB4 produced airway obstruction which was reduced by LY255283 administered i.v. (ED50 = 2.8 mg/kg) or orally (ED50 = 11.0 mg/kg). Contractile responses to histamine, LTD4 and the thromboxane mimetic, U46619, were not reduced by LY255283. The compound also did not inhibit cyclooxygenase or 5-lipoxygenase enzymes. We conclude that LY255283 selectively antagonized pharmacologic responses to LTB4 on lung tissue and appears to be a useful tool to investigate the role of LTB4 in pulmonary disease.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Contributory role of lung pleura to release of anaphylactic mediators from guinea pig lung in response to ovalbumin or A23187.

Previous findings revealed greater contractile responses of guinea pig lung pleural surface strips to antigen or A23187 challenge than denuded lung parenchymal strips (lung strip devoid of any pleura). Moreover, we have identified a high density of mast cells distributed throughout the lung pleura. The present study examined mediators released from guinea pig lung pleural surface and denuded lung parenchyma fragments in response to immunologic challenge with ovalbumin (OA) or non-immunologic challenge with the ionophore A23187. Histamine levels were measured radioenzymatically; leukotrienes (LTs), prostaglandins (PGs) and thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2), were quantitated using an enzyme immunoassay. Histamine release reached a maximal level 3-5 min after OA challenge, whereas A23187-induced histamine release increased gradually in a time-dependent manner. Similar kinetics were observed in the release of LTs, PGs and TXA2. Pleural surface released a substantially (P < 0.05) greater amount of histamine to both challenges than denuded parenchyma. Moreover, histamine content in pleural surface was significantly (P < 0.05) higher than in denuded parenchyma. Pleural surface also released considerably (P < 0.05) more LTB4, LTC4, and LTE4 in response to OA and A23187 than denuded parenchyma. In contrast, pleural surface and denuded parenchyma released equivalent amounts of PGD2, PGE2, PGF2 alpha, and TXA2 in response to both challenges. The rank order of leukotriene release was LTC4 > LTE4 > LTB4, whereas that of prostanoid release was TXA2 >> PGD2 > or = PGF2 alpha >> PGE2. We conclude that pleural surface is the major source of histamine and leukotrienes released from guinea pig lung in vitro in response to OA and A23187, whereas both pleural surface and denuded parenchyma participate to the same extent in prostaglandin and TXA2 production after such challenges.

Animals↗
PubMed1992

Development of a series of phenyltetrazole leukotriene D4 (LTD4) receptor antagonists.

A hypothetical model for receptor binding of leukotriene D4 (LTD4) was deduced from conformational analysis of LTD4 and from the structure-activity relationships (SAR) of known LTD4 receptor antagonists. A new structural series of LTD4 receptor antagonists exemplified by 5-[4-(4-phenylbutoxy)phenyl]-2-[4-(tetrazol-5-yl)butyl]-2H-t etrazole was designed in which a phenyltetrazole moiety was incorporated as a receptor binding equivalent of the triene unit of LTD4. A number of these phenyltetrazoles were prepared and found to possess LTD4 receptor antagonist activity. The structure-activity relationship (SAR) of this series is described.

Animals↗