RESUMO
Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators that predominantly exert their effects by binding to cysteinyl leukotriene receptors of the G protein-coupled receptor family. CysLT receptor 2 (CysLT(2)R), expressed in endothelial cells of some vascular beds, has been implicated in a variety of cardiovascular functions. Endothelium-specific overexpression of human CysLT(2)R in transgenic mice (hEC-CysLT(2)R) greatly increases myocardial infarction damage. Investigation of this receptor, however, has been hindered by the lack of selective pharmacological antagonists. Here, we describe the characterization of 3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)-propoxy)benzoic acid (BayCysLT(2)) and explore the selective effects of this compound in attenuating myocardial ischemia/reperfusion damage and vascular leakage. Using a recently developed ß-galactosidase-ß-arrestin complementation assay for CysLT(2)R activity (Mol Pharmacol 79:270-278, 2011), we determined BayCysLT(2) to be â¼20-fold more potent than the nonselective dual CysLT receptor 1 (CysLT(1)R)/CysLT(2)R antagonist 4-(((1R,2E,4E,6Z,9Z)-1-((1S)-4-carboxy-1-hydroxybutyl)-2,4,6,9-pentadecatetraen-1-yl)thio)benzoic acid (Bay-u9773) (IC(50) 274 nM versus 4.6 µM, respectively). Intracellular calcium mobilization in response to cysteinyl leukotriene administration showed that BayCysLT(2) was >500-fold more selective for CysLT(2)R compared with CysLT(1)R. Intraperitoneal injection of BayCysLT(2) in mice significantly attenuated leukotriene D(4)-induced Evans blue dye leakage in the murine ear vasculature. BayCysLT(2) administration either before or after ischemia/reperfusion attenuated the aforementioned increased myocardial infarction damage in hEC-CysLT(2)R mice. Finally, decreased neutrophil infiltration and leukocyte adhesion molecule mRNA expression were observed in mice treated with antagonist compared with untreated controls. In conclusion, we present the characterization of a potent and selective antagonist for CysLT(2)R that is useful for discerning biological activities of this receptor.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Leucotrieno D4/antagonistas & inibidores , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ácidos Ftálicos/farmacologia , Receptores de Leucotrienos/metabolismo , SRS-A/análogos & derivados , Animais , Arrestinas/análise , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Orelha/irrigação sanguínea , Humanos , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Peroxidase/metabolismo , SRS-A/farmacologia , beta-Arrestinas , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Little is known about the role of the cysteinyl leukotriene (cysLT) 2 receptor in the pathophysiology of asthma. The aim of this study is to investigate the effects of a cysLT1 receptor antagonist (montelukast) and a dual cysLT1/2 receptor antagonist (BAY-u9773) on airway hypersensitivity and airway inflammation induced by antigen challenge in ovalbumin (OVA)-sensitized guinea pigs. METHODS: Male Hartley guinea pigs sensitized with OVA were intraperitoneally administered 0.1, 1, or 10 mg/kg of montelukast or 0.1 mg/kg of BAY-u9773 and then challenged with inhaled OVA. Airway reactivity to acetylcholine, inflammatory cells in bronchoalveolar lavage (BAL) fluid, and eosinophil infiltration in airway walls after OVA challenge were evaluated. RESULTS: Pretreatment with 1 or 10 mg/kg, but not 0.1 mg/kg, of montelukast significantly suppressed airway hypersensitivity and eosinophil infiltration into the BAL fluid. Moreover, 0.1 mg/kg of BAY-u9773 significantly suppressed the development of these markers. The suppressive effects of BAY-u9773, although not significantly different, trended toward being greater than those of montelukast. Although all of the doses of montelukast tested and 0.1 mg/kg of BAY-u9773 significantly suppressed eosinophil infiltration in airway walls, the suppressive effect of BAY-u9773 was significantly greater than that of 0.1 mg/kg of montelukast. CONCLUSION: Signaling may contribute to the pathophysiology of asthma via the cysLT1/2 receptor.
Assuntos
Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/prevenção & controle , Antagonistas de Leucotrienos/uso terapêutico , Receptores de Leucotrienos , Acetatos/farmacologia , Acetatos/uso terapêutico , Acetilcolina/farmacologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/citologia , Ciclopropanos , Eosinófilos/patologia , Cobaias , Inflamação/patologia , Inflamação/prevenção & controle , Antagonistas de Leucotrienos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Quinolinas/farmacologia , Quinolinas/uso terapêutico , SRS-A/análogos & derivados , SRS-A/farmacologia , SRS-A/uso terapêutico , SulfetosRESUMO
The effect of ibudilast on anaphylactic bronchoconstriction was studied in guinea pigs sensitized actively with ovalbumin (OA). Animals were treated with indomethacin, tripelennamine and propranolol prior to the antigen challenge. Anaphylactic bronchoconstriction was prevented by ibudilast (1-4 mg/kg i.v. and 5-20 mg/kg p.o.) dose-dependently. FPL55712 and phenidone were also effective. Even when administered at the maximum development of bronchoconstriction, ibudilast (0.5 and 2 mg/kg i.v.) and FPL 55712 caused significant reduction of the increased airway tone, while phenidone did not. Ibudilast (1-4 mg/kg i.v.) and FPL55712 inhibited leukotriene D4-induced airway responses in nonsensitized guinea pigs pretreated with indomethacin and propranolol. Ibudilast (1.6 and 4 mg/kg i.v.) inhibited platelet-activating-factor (PAF)-induced airway responses in nonsensitized guinea pigs pretreated with indomethacin and propranolol, however, FPL 55712 inhibited PAF-induced airway responses only at a high dose such as 10 mg/kg i.v. Ibudilast (4 mg/kg i.v.) did not inhibit acetylcholine-induced airway response. Ibudilast showed inhibition of the release of slow-reacting substance of anaphylaxis (SRS-A) from guinea pig chopped lung sensitized with OA, which was significantly diminished by indomethacin. The drug little affected the activity of phospholipase A2 and 5-lipoxygenase in guinea pig polymorphonuclear leukocytes. These results indicate that ibudilast inhibits anaphylactic bronchoconstriction which is considered to be largely mediated by endogenously released SRS-A. The inhibitory effect of ibudilast on anaphylactic bronchoconstriction in the presence of indomethacin is considered to be exerted through its antagonism to SRS-A.
Assuntos
Anafilaxia/tratamento farmacológico , Asma/tratamento farmacológico , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Piridinas/farmacologia , Acetilcolina/farmacologia , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Calcimicina/farmacologia , Cromonas/farmacologia , Cobaias , Masculino , Neutrófilos/enzimologia , Fosfolipases A/metabolismo , Fosfolipases A2 , Fator de Ativação de Plaquetas/farmacologia , Pirazóis/farmacologia , SRS-A/farmacologiaRESUMO
The responsiveness of isolated Japanese monkey (Macaca fuscata) tracheal muscle to antigen, carbachol, histamine, leukotriene C4 (LTC4), U-46619 and substance P (SP) was compared to that of isolated human trachea. Weak but persistent contraction was observed after the addition of antigen to isolated Japanese monkey tracheal muscle passively sensitized with monkey serum containing IgE antibody against Japanese cedar (Cryptomeria japonica) antigen. Unlike monkey tracheal muscle, a fair amount of contraction was caused by the antigen in human tracheal muscle passively sensitized with human atopic serum. When chopped, passively sensitized monkey or human lung tissue was challenged with antigen, a significant level of histamine was released from these tissues. In Japanese monkey tracheal muscle, histamine and SP produced no contraction of tracheal muscle, whereas carbachol, LTC4 and U-46619 caused contraction in a dose-dependent fashion. Contrary to the Japanese monkey, histamine and carbachol caused distinct contraction in tracheal muscle obtained from the cotton-headed tamarin (Saguinus oedipus). In human tracheal muscle, all test substances (carbachol, histamine, LTC4, U-46619 and SP) induced clear contraction. In lung parenchyma obtained from Japanese monkey, histamine induced a weak contraction, and this histamine-induced contraction was also inhibited by pyrilamine (H1 receptor antagonist). These results indicate that antigen-induced contraction of isolated Japanese monkey tracheal muscle, passively sensitized with monkey atopic serum, is not a useful model for human allergic bronchoconstriction in vitro because of the unresponsiveness of tracheal muscle to histamine and SP.
Assuntos
Alérgenos/imunologia , Macaca/imunologia , Traqueia/imunologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Carbacol/farmacologia , Liberação de Histamina , Humanos , Imunização Passiva , Técnicas In Vitro , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Ácaros/imunologia , Contração Muscular/efeitos dos fármacos , Pólen/imunologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , SRS-A/farmacologia , Substância P/farmacologia , Traqueia/anatomia & histologiaRESUMO
Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats (47 +/- 2% vs. 54 +/- 1% respectively, P less than 0.01). Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3. Infusion of LTC4 (4 micrograms/kg/min) in normal rats induced a rise in HCT from 44 +/- 1% to 51 +/- 1% (P less than 0.01), which was greater (P less than 0.05) than the rise induced by LTC3 (47 +/- 1% to 49 +/- 1%). The results showing that EFAD rats are resistant to endotoxin-induced increases in HCT and vascular permeability raise the possibility that this may, in part, be a result of preferential LTC3 production that is less potent than LTC4.
Assuntos
Permeabilidade Capilar , Ácidos Graxos Essenciais/deficiência , Choque Séptico/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotoxinas , Eritrócitos , Feminino , Hematócrito , Cinética , Ratos , SRS-A/análogos & derivados , SRS-A/farmacologia , Salmonella enteritidis , Albumina Sérica , Choque Séptico/induzido quimicamente , TecnécioRESUMO
In order to clarify the mechanisms of urtication after contact with stinging plants, nettle (Urtica urens) hair and whole-plant extracts were examined for the presence of leukotriene (LT) B4 and LTC4 by reverse phase high-pressure liquid chromatography (RP-HPLC) and radioimmunoassay (RIA) and for in vitro neutrophil chemotactic activity and histamine contents. Both hair and plant extracts contained high levels of LTB4 and LTC4 by RIA as well as histamine. The presence of LTB4 was supported by RP-HPLC elution profiles and by in vitro chemotaxis. Nettle hairs therefore resemble insect venoms and cutaneous mast cells with regard to their spectrum of mediators.
Assuntos
Leucotrieno B4/imunologia , Plantas Tóxicas/imunologia , SRS-A/imunologia , Alérgenos/análise , Alérgenos/imunologia , Alérgenos/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Humanos , Ácidos Hidroxieicosatetraenoicos/análise , Leucotrieno B4/análise , Leucotrieno B4/farmacologia , Neutrófilos/imunologia , Extratos Vegetais/imunologia , Plantas Tóxicas/análise , Plantas Tóxicas/citologia , SRS-A/análise , SRS-A/farmacologiaRESUMO
Intracerebroventricular (i.c.v.) administration of leukotriene (LT) C4 at doses of 2, 0.5 and 0.2 micrograms/rat significantly stimulated (3-12 fold) the release of LH into the peripheral blood of male rats. Injection of anti-LHRH serum had no effect on LTC4-stimulated LH release, but did block PGE2- stimulated LH release. I.c.v.- infused LTC4 also stimulated the release of LHRH into the hypophyseal portal blood. This is the first report of an in vivo action of LTC4 on the release of a hypothalamic releasing factor (LHRH) and a pituitary hormone (LH). These observations, plus in vitro results, clearly show that LTC4 stimulates LH release by acting on both the hypothalamus, causing LHRH release, and on the pituitary. Then the action of LTC4 on LH release in vivo is quite different from the indirect action of PGE2.
Assuntos
Hormônio Liberador de Gonadotropina/sangue , Hipotálamo/efeitos dos fármacos , Hormônio Luteinizante/sangue , Hipófise/efeitos dos fármacos , SRS-A/farmacologia , Animais , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Injeções Intraventriculares , Hormônio Luteinizante/metabolismo , Masculino , Hipófise/metabolismo , Ratos , Ratos Endogâmicos , SRS-A/administração & dosagemRESUMO
Arachidonic acid metabolites have been shown to modulate the secretion of various hormones, including luteinizing hormone, growth hormone and adrenocorticotropin. In this paper we describe the effect of a series of eicosanoids on hypothalamic secretion of corticotropin-releasing hormone (CRH) in vitro. Explanted rat hypothalami in culture were exposed to prostaglandins (PG) F2 alpha or E2, thromboxane (TX) B2, the TXA2 receptor agonist U-49,619 and leukotrienes (LT) B4, C4 and D4 at concentrations ranging from 10(-15) to 10(-5) M. PGE2, LTD4 and TXB2 did not alter hypothalamic CRH secretion. On the other hand, the remaining eicosanoids tested induced a significant increase of hypothalamic CRH secretion (p less than 0.05). The concentration of 10(-11) M dexamethasone inhibited the effect of stimulatory eicosanoids on CRH secretion. The CRH response to U-49,619 was completely prevented by the TXA2 receptor antagonist SQ-29,548. The latter also inhibited serotonin (5-HT)-, acetylcholine (ACh)- and PGF2 alpha-induced CRH release. Indomethacin was capable of blocking the secretion of CRH induced by 5-HT and ACh. In addition, PGE2 inhibited the increase of CRH secretion induced by PGF2 alpha, 5-HT and ACh. These findings suggest that eicosanoids may be involved in the regulation of hypothalamic CRH secretion, either as autocrine/paracrine or as endocrine factors.
Assuntos
Ácidos Araquidônicos/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Antagonistas de Prostaglandina , Acetilcolina/farmacologia , Animais , Ácido Araquidônico , Compostos Bicíclicos Heterocíclicos com Pontes , Técnicas de Cultura , Dexametasona/farmacologia , Dinoprosta/farmacologia , Dinoprostona/farmacologia , Eicosanoides , Ácidos Graxos Insaturados , Hidrazinas/farmacologia , Hipotálamo/efeitos dos fármacos , Indometacina/farmacologia , L-Lactato Desidrogenase/metabolismo , Leucotrieno B4/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/farmacologia , SRS-A/farmacologia , Serotonina/farmacologia , Tromboxano A2/antagonistas & inibidores , Tromboxano B2/farmacologiaRESUMO
Our previous study showed the inhibitory effect of Qing-Fei-Tang (Q.F.T.) and baicalein on the leukotriene (LT)B4 synthesis of human alveolar macrophages. It has recently been demonstrated that LTs support various cell growth, and basophil and its precursor numbers increase in atopic patients. Therefore, we examined the effect of anti-allergic drugs, including Q.F.T., Xiao-Qing-Long-Tang (X.Q.L.T.), Chai-Pu-Tang (C.P.T.), baicalein and ketotifen which have been used for treatment of bronchial asthma, on human basophil growth in vitro using cord blood mononuclear cells as a basophil precursor source and conditioned medium of T cell leukemia cell line Mo as a growth factor. Two-week cultured basophil numbers identified by alcian blue-safranin staining and those histamine contents assayed fluorometrically were inhibited by Q.F.T. (1.0 mg/ml), X.Q.L.T. (0.01-1.0 mg/ml), C.P.T. (0.01-1.0 mg/ml), baicalein (1-100 microM) or ketotifen (1-100 microM) in a dose-dependent manner while low dose (0.01-0.1 mg/ml) of Q.F.T. showed an enhancing effect on the basophil growth and the histamine content. However, LTB4 or LTC4 failed in restoring the basophil growth reduced by 1 mg/ml of C.P.T. or 100 microM of ketotifen. These results suggest that anti-allergic drugs may modulate basophil growth and differentiation in vitro and/or in vivo and therefore be useful and reasonable for controlling allergic diseases including bronchial asthma.
Assuntos
Basófilos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas , Antagonistas dos Receptores Histamínicos H1 , Basófilos/análise , Basófilos/fisiologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Flavonoides/farmacologia , Histamina/análise , Humanos , Cetotifeno/farmacologia , Leucotrieno B4/farmacologia , SRS-A/farmacologiaRESUMO
The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD4 boluses on the pulmonary circulation in 6 anesthetized dogs. LTD4, 1 microgram/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41 +/- 17% (SD), left atrial pressure rose 3.5 +/- 1.5 mmHg, and cardiac output fell 18 +/- 8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF6 infusion, was 25 +/- 7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O2 inhalation, averaged +10.5 +/- 3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4 +/- 1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26 +/- 4%; p = 0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9 +/- 2.8 mmHg; p less than 0.05; the increase in PVR was +1.8 +/- 1.2 mmHg/L/min, p less than 0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5 +/- 8.1% before and 27.0 +/- 7.4% after RG 5901 (p greater than 0.05). The pressor response to hypoxia was +8.9 +/- 2.1 mmHg before and +8.7 +/- 3.7 mmHg after RG 5901 (p greater than 0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.
Assuntos
Araquidonato Lipoxigenases/antagonistas & inibidores , Hipóxia/fisiopatologia , Cetoácidos , Inibidores de Lipoxigenase , Pulmão/irrigação sanguínea , Circulação Pulmonar/efeitos dos fármacos , Receptores Imunológicos/efeitos dos fármacos , SRS-A/farmacologia , Sulfonas , Vasoconstrição/efeitos dos fármacos , Acetofenonas/farmacologia , Animais , Autacoides/antagonistas & inibidores , Débito Cardíaco/efeitos dos fármacos , Cães , Fenilbutiratos/farmacologia , Artéria Pulmonar , Receptores de Leucotrienos , Tetrazóis/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
Human recombinant interleukin-1 (HrIL-1) inhibited WEHI-3B cell growth in a dose-related manner (10-10,000 U/ml). Prostaglandin E2 at high concentrations (1000 ng/ml) also inhibited cell growth. When added together, HrIL-1 and prostaglandin E2 inhibited WEHI-3B growth in a synergistic manner (HrIL-1 concentrations of 10-10,000 U/ml and prostaglandin E2 concentrations of 10-1000 ng/ml). In contrast to the effects of the cyclooxygenase metabolite of arachidonic acid leukotriene C4, a lipoxygenase metabolite, reversed the cytostatic action of HrIL-1.
Assuntos
Adjuvantes Imunológicos/farmacologia , Dinoprostona/farmacologia , Inibidores do Crescimento/farmacologia , Interleucina-1/antagonistas & inibidores , SRS-A/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Linhagem Celular , Humanos , Interleucina-1/farmacologia , Leucotrieno B4/metabolismo , Proteínas Recombinantes/farmacologia , Tromboxano B2/metabolismo , Células Tumorais Cultivadas/metabolismoRESUMO
The myotropic activities of PAF-acether, leukotriene B4, leukotriene D4 and histamine were compared on superfused guinea-pig lung parenchymal strip and were shown to have the following order of potency: PAF-acether greater than LTD4 greater than LTB4 greater than histamine. The contractile response of the lung parenchyma to PAF-acether was inhibited by aspirin, imidazole and OKY-046, which suggested that thromboxane A2 might play a mediator role in PAF-induced contractions. Neither an antagonist of leukotriene D4, FPL-55712, nor an antihistamine, mepyramine, had any effect on PAF contractions. The activity of a novel antagonist of PAF-acether, BN 52021, was also studied on superfused lung parenchyma contracted by histamine, leukotriene B4, leukotriene D4 and PAF-acether. This compound was without effect on the histamine response but it slightly reduced the contractions elicited by leukotriene D4 and potentiated those by leukotriene B4. BN 52021 (7.1 X 10(-6) M) inhibited by 63% the contraction induced by 5.7 X 10(-13) M PAF-acether and by 52% that induced by 5.7 X 10(-10) M PAF-acether and kadsurenone (8.4 X 10(-6) M), another PAF-acether antagonist, inhibited the same PAF-induced contractions by 75% and 20% respectively.
Assuntos
Diterpenos , Lactonas , Lignanas , Pulmão/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Fator de Ativação de Plaquetas/farmacologia , Antagonistas de Prostaglandina/farmacologia , Animais , Aspirina/farmacologia , Benzofuranos/farmacologia , Cromonas/farmacologia , Ginkgolídeos , Cobaias , Histamina/farmacologia , Imidazóis/farmacologia , Leucotrieno B4/farmacologia , Masculino , Metacrilatos/farmacologia , Músculo Liso/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Pirilamina/farmacologia , SRS-A/farmacologiaRESUMO
The effects of leukotrienes (LT) on production of interleukin 1 (IL 1) by human peripheral blood monocytes were examined. LTB4 enhanced IL 1 production by lipopolysaccharide (LPS)-stimulated monocytes twofold to threefold, and the most efficient concentrations of LTB4 were 10(-8) to 10(-7) M. LTD4 also enhanced IL 1 production, but to a lesser extent than LTB4. Adherence-purified, but otherwise unstimulated, human monocytes could also be induced to produce IL 1 in response to LTB4. Similarly, IL 1 production by monocytes stimulated with the known IL 1 inducers muramyl dipeptide, silica, or zymosan was also enhanced by LTB4. Inhibition of cyclooxygenase with use of indomethacin during IL 1 production by LPS-treated monocytes enhanced thymocyte response to IL 1, but LTB4 further enhanced IL 1 production when added to indomethacin-treated monocyte cultures. Neither LTB4 nor indomethacin had any direct effect on thymocyte proliferation. Optimal enhancement of IL 1 production occurred when LPS and LTB4 were present together at the initiation of the 24-hr monocyte culture. Significant enhancement was also observed, however, when monocyte cultures were either preincubated with LTB4 before addition of LPS or cultured with LPS alone for 3 hr before addition of LTB4. These results indicate that leukotrienes can modulate IL 1 production by human monocytes and suggest that they may play a role in IL 1-mediated functions of monocytes in inflammatory and immune reactions.
Assuntos
Adjuvantes Imunológicos/farmacologia , Interleucina-1/biossíntese , Leucotrieno B4/farmacologia , Monócitos/metabolismo , SRS-A/farmacologia , Humanos , Cinética , Lipoxigenase/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacosRESUMO
Slow reacting substance of anaphylaxis (SRS-A) is an important chemical mediator of bronchial asthma. Leukotriene C4 is a component of SRS-A and is synthesized from arachidonic acid. Its synthesizing and releasing processes are found to be Ca2+-dependent. We developed an in vivo inhalation asthma model, mainly mediated by SRS-A, and elucidated the relationship between a Ca2+-antagonist, nicardipine, and SRS-A. In the asthmatic model, mediated by endogenous SRS-A induced by antigen inhalation, continuous intravenous infusion of nicardipine 7 micrograms/kg/min depressed the open airway pressure by about 60% compared with the saline-treated group. Inhibition of mean pulmonary resistance (RL) was about 50% and that of the inverted value of dynamic compliance (1/Cdyn) about 36%. However, the same concentration of nicardipine did not significantly effect the airway response in the asthmatic model induced by the inhalation of leukotriene C4. These results suggest that nicardipine, at the concentration used in the present study. did not block the direct effect of SRS-A on the smooth muscle, but blocked the Ca2+ influx required for the synthesis of SRS-A and its release.
Assuntos
Asma/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Nifedipino/análogos & derivados , SRS-A/biossíntese , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Antígenos/administração & dosagem , Asma/imunologia , Asma/fisiopatologia , Cobaias , Masculino , Nicardipino , Nifedipino/uso terapêutico , Ovalbumina/imunologia , SRS-A/metabolismo , SRS-A/farmacologiaRESUMO
Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C4 and D4 administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C4, D4, and E4 into the coronary artery of the domestic pig. Increasing doses (0.1, 0.3, 1.0, and 3.0 micrograms) of leukotrienes C4, D4, and E4 were injected into the left anterior descending coronary artery of 8 open-chest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean +/- standard error); C4 = 80 +/- 9%, p less than 0.001; D4 = 81 +/- 3%, p less than 0.001; E4 = 64 +/- 12%, p less than 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 micrograms) of leukotrienes C4 and D4. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection. We conclude that leukotrienes C4, D4, and E4 are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory changes.
Assuntos
Circulação Coronária/efeitos dos fármacos , SRS-A/análogos & derivados , SRS-A/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Doença das Coronárias/induzido quimicamente , Relação Dose-Resposta a Droga , Cobaias , Hemodinâmica/efeitos dos fármacos , Leucotrieno E4 , Contração Miocárdica/efeitos dos fármacosRESUMO
The lipoxygenase products of arachidonic acid, 5-HPETE, 5-HETE, LTB4, LTC4 and LTD4, were examined for their capacity to enhance the expression of complement (C3b) receptors and to evoke chemotaxis of human neutrophils and eosinophils. With the exception of LTD4 all gave enhancement of C3b receptors. LTB4 and LTC4 enhanced over the concentration range 10(-7) to 10(-11) moles/l, and 5-HETE and 5-HPETE from 5 X 10(-6) to 5 X 10(-10) moles/l. The rank order of activity, as assessed by the magnitude of enhancement, was LTB4 (concentration for maximal effect = 10(-7) moles/l) greater than 5-HETE (5 X 10(-7)) greater than 5-HPETE (5 X 10(-6)) greater than LTC4 (10(-9)). High dose inhibition was observed with LTC4 and 5-HETE. Chemotaxis experiments performed in parallel over the same concentration ranges indicated that neither neutrophils nor eosinophils migrated towards LTC4 or LTD4. However, LTB4 evoked chemotaxis with a linear dose response from 10(-9) to 10(-7) moles/l and 5-HPETE and 5-HETE from 5 X 10(-8) to 5 X 10(-6) moles/l. At 10(-7) moles/l LTB4 was approximately 6 and 8 X more potent in chemotaxis than 5-HPETE and 5-HETE respectively. In general, complement receptor enhancement and chemotaxis of eosinophils were similar to that observed with neutrophils and did not vary with the patient source.