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PubMed1995

Visualization and comparison of molecular dynamics simulations of leukotriene C4, leukotriene D4, and leukotriene E4.

Molecular dynamics simulations of leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4) were carried out, and the data were visualized in an animated video format. Three-dimensional ghost images show the positions of the heavy atoms of all three molecules throughout the simulations. The ghost images can be superimposed to give a single three-dimensional image in which the shapes of the most populated conformers of each molecule are apparent and can be compared. Leukotriene D4 was found to occupy mostly T-shaped conformations, while LTC4 occupied mostly cup-shaped conformations, and LTE4 occupied a wide range of conformations spanning the LTD4 and LTC4 types. Digital filtering and graphing of the internal geometries of the molecules as a function of time revealed differences in dynamic behavior. The results are discussed in light of current knowledge about leukotriene receptors.

Computer Graphics↗
PubMed1990

SK&F S-106203 inhibits leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

1. The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F S-106203, on leukotriene C4 (LTC4), LTD4 and LTE4 vasopressor responses in the conscious, normotensive rat. SK&F S-106203 was administered as a bolus followed by a continuous infusion in order to provide information on the relationship between antagonism of leukotriene responses and steady-state plasma concentrations. 2. Infusion of SK&F S-106203 at doses of 0.2 mgkg-1 + 1 mgkg-1 h-1, 1 mgkg-1 + 3 mgkg- h-1 or 2 mgkg-1 + 10 mgkg-1 h-1 produced dose-dependent steady-state plasma drug concentrations of 1.0, 3.2 and 23.8 micrograms ml-1, respectively. Plasma SK&F S-106203 concentrations appeared to increase in a linear fashion at doses of 1 and 3 mgkg-1 h-1; at the highest dose the increment in plasma drug concentrations (i.e., 7-8 fold) was greater than the increment in dose (i.e., 3 fold), suggesting saturation of the primary clearance mechanism(s) at this dose. 3. SK&F S-106203 (2 mgkg-1 + 10 mgkg-1 h-1) had no effect on noradrenaline-, vasopressin-, isoprenaline-, or U 46619-induced responses. 4. SK&F S-106203 produced dose-dependent rightward shifts in the LTC4 and LTE4 dose-response curves. Administration of SK&F S-106203 at doses of 0.2mg kg1 + 1 mg kg1 h-, mg kg' + 3mgkg-'h-1, or 2mgkg-' + lOmgkg-1h'- produced dose-ratios of 1.0, 3.1 and 19.9, respectively, against LTC4 responses, and dose-ratios of 1.6, 3.8 and 9.1, respectively, against LTE4 responses. 5. Against LTD4 responses, SK&F S-106203 at doses of 0.2mgkg- + mgkg-1 h-, mg kg' + 3 mg kg- 1h - ', or 2 mg kg- + 10 mg kg- h- produced dose-ratios of 2.5, 2.8, and 11.4, respectively. Administration of D-penicillamine, a non-competitive LTD4 dipeptidase inhibitor, had no effect on LTD4 responses. 6. The similarity in the LTD4 dose-ratios at the two lower infusion rates, despite increases in the plasma drug concentrations, suggests the existence of pharmacologically heterogeneous LTD4 receptors. These results indicate that SK&F S-106203 is a potent, selective and apparently competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the intact rat.

Animals↗
PubMed1988

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.

Animals↗
PubMed1989

Antagonism of leukotriene C4, leukotriene D4 and leukotriene E4 vasoconstrictor responses in the conscious rat with the peptidoleukotriene receptor antagonist SK&F 104353: evidence for leukotriene D4 receptor heterogeneity.

The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F 104353, on leukotriene (LT)C4, LTD4 and LTE4 vasopressor responses in conscious, normotensive rats. Steady-state plasma concentrations of SK&F 104353 at infusion rates of 0.2 mg/kg + 1 mg/kg/hr, 1 mg/kg + 3 mg/kg/hr or 2 mg/kg + 10 mg/kg/hr were 0.5, 1.6 and 9.4 micrograms/ml, respectively, indicating that the plasma concentrations of SK&F 104353 were related directly to the infusion rate. LTC4, LTD4 and LTE4 (0.17-170 nmol/kg i.v.) produced dose-dependent increases in mean blood pressure. The ED20 dose (i.e., dose required to increase blood pressure 20 mm Hg) of LTC4, LTD4 or LTE4 was 2.7 +/- 0.4, 2.2 +/- 0.3 and 109 +/- 17 nmol/kg, respectively. SK&F 104353 produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. Administration of SK&F 104353 at doses of 0.2 mg/kg + 1 mg/kg/hr, 1 mg/kg + 3 mg/kg/hr or 2 mg/kg + 10 mg/kg/hr produced dose ratios (i.e., ratio of ED20 in presence of SK&F 104353 to that of the vehicle group) of 6, 12 and 26, respectively. Against LTD4 responses, SK&F 104353 at doses of 0.1 mg/kg + 0.3 mg/kg/hr or 0.2 mg/kg + 1 mg/kg/hr produced dose ratios of 3 and 9, respectively. At a dose of 1 mg/kg + 3 mg/kg/hr, there was no further increase in the dose ratio, whereas a dose of 2 mg/kg + 10 mg/kg/hr resulted in a dose ratio of greater than 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

ICI 198615 is an antagonist of leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

The purpose of these studies was to evaluate the effects of the peptidoleukotriene (LT) receptor antagonist, ICI 198615, on the vasopressor responses produced by LTC4, LTD4 and LTE4. Conscious, normotensive rats were prepared with arterial and venous catheters for measurement of changes in arterial blood pressure and administration of drugs, respectively. Complete dose-response curves were first generated to LTC4, LTD4 and LTE4: those agents produced dose-dependent increases in arterial blood pressure, with ED20 values (i.e. dose to increase blood pressure 20 mm Hg) of 1.7 +/- 0.2, 2.1 +/- 0.2 and 19.8 +/- 3.7 nmol/kg i.v., respectively. ICI 198615 (intravenous bolus followed by a continuous infusion) produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. At doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h, ICI 198615 produced dose ratios of 4.5, 17.1 and 50.0, respectively. Against LTD4 responses, ICI 198615 at a dose of 0.1 mg/kg + 0.3 mg/kg/h produced a dose ratio of 3.4, whereas at doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h ICI 198615 produced dose ratios of 16.3, 24.9 and 16.2, respectively. The difference in the dose ratios between these three groups was not statistically significant (p greater than 0.05). However, a dose of 10 mg/kg + 30 mg/kg/h produced a dose ratio of greater than 100. Against LTE4 responses, ICI 198615 at doses of 0.2 mg/kg + 1 mg/kg/h or 1 mg/kg + 3 mg/kg/h produced dose ratios of 4.1 and 11.3, respectively. The similarity in the LTD4 dose ratios despite a 3- or 10-fold increase in the dose of ICI 198615 suggests the existence of high- and low-affinity LTD4 receptor sites, whereas the responses to LTC4 and LTE4 appeared to be mediated via a single receptor population. These results indicate that ICI 198615 is a potent and competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the rat.

Animals↗
PubMed1993

Influence of atherosclerosis on the vascular reactivity of isolated human epicardial coronary arteries to leukotriene C4.

Leukotrienes, lipid mediators derived from arachidonic acid by the 5-lipoxygenase pathway, have been implicated in a variety of myocardial ischemic events including myocardial infarction and coronary spasm. We have examined the comparative effects of leukotriene C4 in isolated human non-atherosclerotic and atherosclerotic coronary arteries to gain an insight into the role of leukotrienes in coronary heart disease. Human coronary arteries, obtained from recipient hearts at the time of cardiac transplantation, were cut into rings and examined in an isolated organ bath. In atherosclerotic arteries leukotriene C4 (1nM-100nM) produced a maximal contractile response of 54.9 +/- 7.98% KCI (n = 7) and the mean EC50 value was 11.1nM (95% confidence interval: 9.4-13.0). The leukotriene receptor antagonist ICI-198,615 (3 x 10(-8)M) produced an approximate 50-fold rightward shift of the leukotriene C4 dose-response curve (n = 5). In contrast, non-atherosclerotic arteries were either non-responsive (n = 5) or only weakly responsive (n = 2) to leukotriene C4 (1nM-100nM), producing an average maximum response of 3.65 +/- 3.05% KCI (n = 7; p < 0.01 atherosclerotic vs non-atherosclerotic). In the presence of indomethacin and in vessels denuded of endothelium, non-atherosclerotic arteries remained unresponsive to leukotriene C4 (n = 3). In addition, leukotriene C4 did not relax preconstricted vessels (n = 7). In vitro autoradiography showed specific [3H]-leukotriene C4 binding to smooth muscle in both non-atherosclerotic and atherosclerotic arteries, with no evidence of endothelium-dependent binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Enzymatic barrier protects brain capillaries from leukotriene C4.

Leukotriene C4 (LTC4) increases vascular permeability in systemic, brain tumor, and ischemic brain capillaries, but not in normal brain capillaries. This study examines whether the abundance of gamma-glutamyl transpeptidase (gamma-GTP) in normal brain capillaries might act as an enzymatic barrier to vasoactive leukotrienes in the brain. Blood-brain barrier (BBB) permeability was determined by quantitative autoradiography using 14C-aminoisobutyric acid. Ischemia was produced by occluding the middle cerebral artery. Seventy-two hours after occlusion, gamma-GTP activity in ischemic brain disappeared, and LTC4 (4-micrograms total dose), which was infused into the carotid artery ipsilateral to the occlusion, selectively increased permeability, Ki, approximately twofold within core ischemic tissue and adjacent tissue, compared to vehicle alone in seven brains (15.53 +/- 6.03 vs. 7.29 +/- 3.36, p < 0.05, and 8.76 +/- 4.02 vs. 4.32 +/- 2.65, p < 0.05, respectively). No effect on BBB was seen in nonischemic brain tissue. Twenty-four hours postocclusion, gamma-GTP activity was still present, and LTC4 infusion did not increase permeability within ischemic tissue. However, inhibition of gamma-GTP with acivicin allowed LTC4 to increase permeability even 24 hours after occlusion in ischemic core and adjacent tissue compared to vehicle alone in seven brains (17.21 +/- 16.32 vs. 8.23 +/- 6.58, p < 0.05, and 11.78 +/- 7.96 vs. 4.56 +/- 1.93, p < 0.01, respectively). Acivicin almost completely blocked both the histochemical activity of gamma-GTP in brain capillaries and the metabolism of LTC4 in isolated bovine capillaries. These findings suggest that gamma-GTP may help normal brain capillaries resist the vasoactive effects of LTC4. In contrast, gamma-GTP is lost in injured brain capillaries, which allows LTC4 (in combination with other factors) to increase vascular permeability in ischemic brain and brain tumors.

Animals↗
PubMed1984

Rapidly-adapting receptor activity and intratracheal pressure in guinea pigs. I. Action of leukotriene C4.

Leukotriene C4 (LTC4) is a major component of slow-reacting substance of anaphylaxis (SRS-A) and is a potent bronchoconstrictor. In humans LTC4 results in bouts of coughing which suggests stimulation of pulmonary receptors involved in a reflex mechanism. Furthermore, atropine reduces the effect of both LTC4 and SRS-A. To test the hypothesis that LTC4 stimulates the rapidly-adapting or "irritant" receptor (RAR) of the airways, we administered LTC4 by both intravenous injection (10-1000 ng) and by aerosol delivery (1 microgram/ml) to the lungs of guinea pigs while recording arterial blood pressure, intratracheal pressure, and nerve activity from RARs. LTC4 (i.v.) concurrently increased both nerve activity and intratracheal pressure even at low doses in a dose-dependent manner. Therefore, a direct action of LTC4 (i.v.) upon the RAR is difficult to conclude. The separation of peak tracheal pressure and peak nerve activity was apparent with aerosol delivery of LTC4. The pattern of RAR activity during LTC4 aerosol challenge was unrelated to respiratory phase. FPL 55712 blocks the effects of SRS-A. We challenged the lung with 500 ng LTC4 intravenously before and after FPL 55712 injection (2.5 mg/kg). FPL 55712 blocked the increases of both tracheal pressure and RAR activity.

Aerosols↗
PubMed1990

Behavioral and physiological effects of leukotriene C4.

Leukotriene C4 (LTC4), a lipoxygenase metabolite of arachidonic acid, is a biological mediator of vasoregulation, pulmonary activity, shock, and inflammation, that has been demonstrated to have radioprotective efficacy. The effects of LTC4 on locomotor activity, rectal temperature and hematocrit were examined. Subcutaneous administration of doses of 1.0 micrograms LTC4/mouse or less did not affect locomotor activity. Doses of 5 or 10 micrograms LTC4/mouse, however, resulted in almost complete cessation of locomotion within 12-14 min following treatment. At these doses, activity was suppressed for 2 h with complete recovery by 3 h postinjection. While a dose as high as 10 micrograms LTC4 did not affect rectal temperature, 5 and 10 micrograms LTC4 resulted in hematocrit increases of 10% and 40% respectively. Hematocrit returned to baseline within 1 h after a 5 micrograms pretreatment of LTC4, and by 3 h following a 10 micrograms pretreatment. The duration of LTC4-induced locomotor suppression did not correlate with previously determined durations of LTC4-induced radioprotection.

Animals↗
PubMed1993

Airway responsiveness to leukotriene C4 (LTC4), leukotriene E4 (LTE4) and histamine in aspirin-sensitive asthmatic subjects.

We wanted to determine whether the airway response to inhaled leukotriene C4 (LTC4) is similar to inhaled leukotriene E4 (LTE4) in aspirin-sensitive asthma and, therefore, determined airway responsiveness to histamine, LTC4 and LTE4 in seven aspirin-sensitive subjects and 13 control asthmatic subjects, who were tolerant of aspirin. The concentration of inhaled lysine-aspirin which produced a 15% fall in forced expiratory volume in one second (FEV1) (PC15) was determined in aspirin-sensitive asthmatic subjects. The dose of histamine, LTC4 and LTE4 which produced a 35% fall in specific airways conductance (PD35sGaw) was determined by linear interpolation from the log dose response curve. There was no correlation between the PC15 for lysine-aspirin and the airway reactivity to inhaled LTC4 or LTE4. There was no difference in airway response to histamine and LTC4 between any of the groups of asthmatic subjects. There was a rank order of potency LTC4 > LTE4 > histamine in both groups, with LTC4 approximately 1,000 fold more potent than histamine in both groups. Aspirin-sensitive asthmatic subjects were significantly more responsive to LTE4 (p = 0.02) than aspirin-tolerant asthmatic subjects. The relative responsiveness of LTE4 to histamine (PD35 histamine/PD35 LTE4) was significantly greater in aspirin-sensitive asthmatic subjects compared to aspirin-tolerant asthmatic subjects (p = 0.05). There was no difference in relative responsiveness of LTC4 to histamine between aspirin-sensitive or aspirin-tolerant asthmatic subjects. We conclude that the airways of aspirin-sensitive asthmatic subjects demonstrate a selective hyperresponsiveness to LTE4, which is not observed for LTC4.

Adolescent↗
PubMed1995

Cardiovascular effects of N-methyl leukotriene C4, a nonmetabolizable leukotriene C4 analogue, and the antagonism of leukotriene-induced hypotension by Ro 23-3544, in the American bullfrog, Rana catesbeiana.

Although some leukotriene antagonists have been reported to block leukotriene (LT) C4 responses in vivo, it is difficult to determine whether those antagonists block the effect of LTC4 directly or act via blocking the action of LTD4, as LTC4 is metabolized to LTD4 rapidly in vivo. In this study, the dose-response curves of N-methyl LTC4 (NMLTC4), the nonmetabolizable LTC4 analogue, and the peptidoleukotrienes (LTC4, LTD4, and LTE4) were obtained in the absence and presence of the leukotriene antagonist Ro 23-3544 in cannulated frogs. The more potent effect of NMLTC4 suggests that receptors that preferentially bind LTC4 exist in frog vascular smooth muscle and the previously reported LTC4 effect is a combination of LTC4 and its less potent metabolite LTD4. The NMLTC4- and LTC4-induced hypotensive effects were antagonized by Ro 23-3544. Ro 23-3544 also antagonized the effects induced by high doses of LTD4 and LTE4. Ro 23-3544 had no effect on duration of response and did not affect heart rate responses to LTC4 at low dose of the antagonist. The data suggest that receptors that preferentially bind LTC4 in bullfrog vascular smooth muscle regulate the hypotensive effect and that they can be antagonized by Ro 23-3544.

Animals↗
PubMed1985

The binding of leukotriene C4 and leukotriene D4 to membranes of a smooth muscle cell line (BC3H1) and evidence that leukotriene induced contraction in these cells is mediated by thromboxane, protein and RNA syntheses.

Leukotriene C4 (LTC4) and leukotriene D4 (LTD4) are important mediators of anaphylaxis and induced thromboxane (TxA2) synthesis in vivo and in vitro. The mechanism by which this occurs is not known and the cellular source of leukotriene (LT) induced TxA2 has not been identified. To obtain insights into this problem we have established an in vitro system using the BC3H1 murine smooth muscle cell line. A membrane fraction obtained from these cells contained binding sites for [3H]LTC4 having high specificity and affinity. Binding of [3H]LTC4 was saturable, specific and reversible with a dissociation constant (KD) of 33 +/- 16 nM and a maximum number of binding sites (Bmax) of 25 +/- 6 pmol/mg membrane protein. However, the amount of [3H]LTD4 specifically bound was considerably less than that of [3H]LTC4. LTC4 and LTD4 induced these cells to contract, a process which was blocked by inhibitors of cyclooxygenase and thromboxane synthetase. Using a radioimmunoassay, we have shown that the level of TxB2 (a stable metabolite of TxA2) was increased in response to LTC4 and LTD4 treatment in a dose-dependent manner. Cycloheximide, a protein synthesis inhibitor, and actinomycin D, an inhibitor of RNA synthesis, were found to inhibit both LTC4- and LTD4-induced TxB2 synthesis and cellular contraction. Arachidonic acid, in the absence of LT, increased the levels of TxB2 synthesis and contraction even in the presence of cycloheximide and actinomycin D. These data are consistent with the hypothesis that the rate-limiting step in LT-induced TxB2 synthesis is the formation of free arachidonic acid, a process which requires RNA and protein synthesis.

Animals↗
PubMed1991

Induction of plasma exudation and inflammatory cell infiltration by leukotriene C4 and leukotriene B4 in mouse peritonitis.

Leukotriene induction of the fluid and cellular phases of the inflammatory response in the mouse was evaluated. Intraperitoneal injection of leukotriene C4 (LTC4 250 ng) led to dye extravasation but not polymorphonuclear leukocyte (PMN) infiltration, whereas injection of leukotriene B4 (LTB4 250 ng), led to PMN infiltration but not dye extravasation. The injection of both leukotrienes did not result in synergy. LTC4 did not appear to induce significant release or formation of chemotactic mediators, but the dye extravasation induced by LTC4 was inhibited by the vasoactive amine antagonist cyproheptadine and not by the eicosanoid inhibitors phenidone or naproxen. The response was markedly inhibited by the cytokine and eicosanoid inhibitors SK&F 86002 and SK&F 104493. PMN infiltration induced by LTB4 was not inhibited by SK&F 86002 or phenidone but was abrogated by colchicine treatment. LTB4 in this model did not appear to cause release or formation of vasoactive mediators. These leukotrienes appeared to be independent, complementary, and sufficient to mount a complete inflammatory response in the mouse.

Animals↗
PubMed1995

Effect of a selective thromboxane A2 receptor antagonist BAY u3405 on antigen-, leukotriene C4- and leukotriene D4-induced bronchoconstriction in guinea pigs.

We studied the effect of a selective thromboxane (TX) A2 receptor antagonist BAY u3405 on prostanoid-, leukotriene (LT) C4, LTD4- and antigen-induced bronchoconstriction in nonanesthetized guinea pigs in vivo. Oral administration of BAY u3405 inhibited bronchoconstriction induced by inhaled TXA2 mimetic U46619, prostaglandin (PG) D2 and PGF2 alpha. BAY u3405 also decreased the bronchoconstriction induced by inhaled LTC4 and LTD4. Intraperitoneal administration of TXA2 synthetase inhibitor OKY-046 did not affect PGD2- and PGF2 alpha-induced bronchoconstriction, but attenuated LTC4- and LTD4-induced bronchoconstriction. BAY u3405 and OKY-046 decreased antigen-induced bronchoconstriction in actively sensitized guinea pigs. These results indicate that BAY u3405 not only inhibits TXA2-, PGD2- and PGF2 alpha-induced bronchoconstriction that is mediated through a TXA2 receptor but also decreases LTC4. LTD4- and antigen-induced bronchoconstriction which is mediated in part through TXA2 synthesis. These results suggest that BAY u3405 might be useful in controlling prostanoid-induced bronchoconstriction in asthma.

Animals↗
PubMed1994

Inhibition by a novel peptide leukotriene receptor antagonist ONO-1078 of airway wall thickening and airway hyperresponsiveness to histamine induced by leukotriene C4 or leukotriene D4 in guinea-pigs.

We studied the effect of intravenous administration of leukotriene (LT) C4 or LTD4 on airway responsiveness to histamine and airway wall thickening in guinea-pigs. Guinea-pigs were killed and the lungs were fixed in formalin. Slides from paraffin-embedded section of the lungs were stained and the airways that were cut in transverse section were measured by tracing enlarged images using a digitizer. Moreover, airway resistance (Raw) was determined by a pulmonary mechanics analyser and we calculated two indices, an index of airway wall thickening and the one of airway hyperresponsiveness to histamine, from changes of baseline-Raw and peak-Raw following intravenous administration of histamine before and after the intravenous administration of LTC4 or LTD4. The infusion of LTC4 or LTD4 induced an increase of the relative thickness of the airway wall in peripheral bronchi demonstrable by the histological examination. In analysis of airway function, intravenous administration of LTC4 or LTD4 induced airway hyperresponsiveness to histamine with airway wall thickening. The LTC4 and LTD4 receptor antagonist ONO-1078 inhibited these effects of LTC4 and LTD4, suggesting LTC4 and LTD4 may induce airway wall thickening and airway hyperresponsiveness through LTC4 and LTD4 receptors in the airways.

Airway Resistance↗
PubMed1984

Effect of the serine-borate complex on the relative ability of leukotriene C4, D4 and E4 to inhibit lung and brain [3H] leukotriene D4 and [3H] leukotriene C4 binding: demonstration of the agonists' potency order for leukotriene D4 and leukotriene C4 receptors.

To define the potency order of the leukotrienes for inhibition of [3H] leukotriene D4 and [3H] leukotriene C4 binding, we investigated leukotriene C4, D4 and E4 competition with and without the serine-borate complex in guinea pig lung and brain homogenates. Without it, the rank order of their potency for inhibition of lung [3H] leukotriene D4 or [3H] leukotriene C4 binding was leukotriene C4 = leukotriene D4 greater than leukotriene E4. Presence of the complex altered the potency order for both competition studies: for the [3H] leukotriene D4 competition it was leukotriene D4 greater than leukotriene E4 = leukotriene C4 and for the [3H] leukotriene C4 competition it was leukotriene C4 much greater than leukotriene D4 greater than or equal to leukotriene E4.

Animals↗
PubMed1995

Taurocholate-stimulated leukotriene C4 biosynthesis and leukotriene C4-stimulated choleresis in isolated rat liver.

BACKGROUND/AIMS: Cysteinyl-containing leukotrienes seem to exert a cholestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for leukotrienes in bile flow formation. METHODS: In the isolated rat liver, the effects of two different concentrations of leukotriene C4 on bile flow and bile salt excretion are analyzed, as well as the possible effect of taurocholate on the hepatic production of cysteinyl-containing leukotrienes. RESULTS: Leukotriene C4 (0.25 fmol) increased bile salt excretion (+22.2%; P < 0.05), whereas a much higher dose (0.25 x 10(6) fmol) showed the known cholestatic effect, reducing bile salt excretion (-25.9%; P < 0.01). These dose-dependent biphasic effects were specific because they could be prevented by the simultaneous administration of cysteinyl-containing leukotriene antagonists. On the other hand, taurocholate administration induced a dose-dependent increase in biliary excretion of cysteinyl-containing leukotrienes. Furthermore, taurocholate increased messenger RNA levels of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Taurocholate increase of hepatocyte intracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism. CONCLUSIONS: These results constitute evidence for the existence of a positive feedback mechanism by which bile salts stimulate the synthesis of leukotrienes that, in turn, stimulate bile salt excretion.

Animals↗