RESUMO
Racemic 6-[4-(3'-hydroxy-1'-octenyl)-3-pyridyloxy]hexanoic and 6-[4-(3'-hydroxyoctyl)-3-pyridyloxy] exanoic acids have been synthesized and their activity as inhibitors of the biosynthesis of thromboxane A2 in human serum has been studied, in comparison with isomers having the eight-carbon chain in the 2 position. Very high, selective activity was found for the new 4-substituted 3-pyridinol ethers, whereas the 2-substituted compounds showed no action.
Assuntos
Piridinas/farmacologia , Tromboxano B2/biossíntese , Tromboxano-A Sintase/antagonistas & inibidores , Depressão Química , Dinoprostona , Humanos , Prostaglandinas E/biossínteseRESUMO
The five stable metabolites [prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha)] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in M5076 ovarian reticulosarcoma (M5) homogenates at various times after tumor implantation (Days 15, 18, 21, and 24). Vegetating tumor showed an active AA overall metabolism, which significantly increased during tumor growth. Synthesis of selected products (TXB2, PGD2, and PGE2) increased markedly over time (up to 10.6, 3.5, and 0.9 micrograms/g, respectively). The overall metabolic profile was TXB2 much greater than PGD2 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than PGE2 on Day 15 and TXB2 much greater than PGD2 much greater than PGF2 alpha greater than 6-keto-PGF1 alpha on Day 24. TXB2 was also by far the most abundant product of in vitro-cultured M5 cells. Chronic treatment of M5-bearing mice with dazmegrel (UK-38,485), a selective thromboxane synthetase inhibitor (100 mg/kg p.o. daily, from Day 7 to killing), resulted in incomplete TXB2 synthesis inhibition, AA metabolism diversion toward the other prostaglandins, and no effects of tumor growth and metastasis. More frequent dazmegrel treatment (100 mg/kg p.o. every 8 h from Day 1 to killing) resulted in complete TXB2 synthetase inhibition, AA metabolism diversion, and increased tumor growth and metastasis. These data do not support the hypothesis of thromboxane synthetase inhibitors reducing tumor growth. However, since TXB2 suppression was accompanied by the production of other products possibly interfering in tumor growth, no conclusions on the effective role of TXA2 in malignancy can be drawn.
Assuntos
Imidazóis/farmacologia , Linfoma não Hodgkin/metabolismo , Neoplasias Ovarianas/metabolismo , Prostaglandinas/biossíntese , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxanos/biossíntese , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Dinoprostona , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Prostaglandina D2 , Prostaglandinas D/biossíntese , Prostaglandinas E/biossíntese , Tromboxano B2/biossínteseRESUMO
The five stable metabolites [prostaglandin F2 alpha, prostaglandin D2, prostaglandin E2 (PGE2), thromboxane B2, and 6-keto-prostaglandin F1 alpha] of arachidonic acid (AA) via the cyclooxygenase pathway were measured by high-resolution gas chromatography-mass spectrometry in Lewis lung carcinoma homogenates at various times after tumor implantation (11 to 25 days). Vegetating and necrotic sections of the primary tumor and lung metastases were examined. Vegetating tumor showed a very active AA metabolism. Synthesis of PGE2, the most abundant product, markedly increased during tumor growth (up to 30 micrograms/g). A high and increasing synthetic capacity was also noted for prostaglandin D2 (up to 9 micrograms/g). Minor time differences and lower levels (up to 1.4 micrograms/g) were found for the other AA metabolites. PGE2 and prostaglandin D2 were the major products in necrotic tumor, too, but synthesis was markedly less than in vegetating tumor, and no increase was noted over time. Metastatic tissue showed a different AA metabolic profile, as compared to primary tumor and surrounding lung tissue, with PGE2 and 6-keto-prostaglandin F1 alpha being the main metabolites.
Assuntos
Neoplasias Pulmonares/metabolismo , Prostaglandinas/biossíntese , Tromboxanos/biossíntese , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The left anterior descending coronary artery (LAD) of five dogs was ligated, and blood was withdrawn from the great cardiac vein, left marginal cardiac vein, femoral vein, and aorta. After ligation, immunoreactive 6-ketoprostaglandin (PG) F1 alpha rose from less than 0.1 to a mean value of 1.2 pmol/ml plasma in the great cardiac vein (GCV) and 0.88 pmol/ml in the left marginal vein, with no change in peripheral circulation. Immunoreactive thromboxane (TX) B2 remained below 0.075 pmol/ml throughout the experiments. LAD of 11 dogs was stenosed 60-80% with consequent cyclical reductions in blood flow. 6-Keto-PGF1 alpha in GCV rose in seven dogs (range 0.5-2.2 pmol/ml) and remained unchanged in four. No change was observed in peripheral plasma levels of 6-keto-PGF1 alpha. In these experimental conditions TXB2 remained below 0.075 pmol/ml. Lactate concentrations rose in both experimental conditions in GCV but not in peripheral circulation or in the left marginal vein. This study confirms a link between cardiac ischemia and increased coronary prostacyclin release, but we were unable to detect a similar correlation with TXB2 in plasma.
Assuntos
6-Cetoprostaglandina F1 alfa/sangue , Circulação Coronária , Doença das Coronárias/sangue , Tromboxano B2/sangue , Tromboxanos/sangue , Animais , Artérias , Constrição Patológica/fisiopatologia , Doença das Coronárias/patologia , Doença das Coronárias/fisiopatologia , Cães , Ligadura , MasculinoRESUMO
Selective pharmacological blockade of thromboxane-synthase in human platelets by dazoxiben resulted in the reorientation of cyclic-endoperoxides towards PGE2, PGD2 and PGF2 alpha. At concentrations which can be reached when thromboxane-synthase is inhibited, PGE2 (100-500 nM) exerted a marked, concentration-dependent pro-aggregatory effect. This required the formation of endogenous or the addition of exogenous endoperoxides and was prevented by PGD2 or 13-aza-prostanoic acid, a selective antagonist of PGH2/TxA2 receptors. The anti-aggregating effect of PGD2 was evident at concentrations lower than those obtained in dazoxiben-treated platelets. It is proposed that in the absence of TxA2 generation, a combination of endoperoxides and PGE2 may result in normal aggregation. The latter may be inhibited by PGD2. No interference of PGF2 alpha on platelet function could be shown.
Assuntos
Plaquetas/enzimologia , Oxirredutases/antagonistas & inibidores , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Difosfato de Adenosina/farmacologia , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Dinoprosta , Dinoprostona , Sinergismo Farmacológico , Humanos , Imidazóis/farmacologia , Prostaglandina D2 , Endoperóxidos de Prostaglandina/metabolismo , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Prostaglandinas D/metabolismo , Prostaglandinas D/farmacologia , Prostaglandinas E/metabolismo , Prostaglandinas E/farmacologia , Prostaglandinas F/metabolismo , Prostaglandinas F/farmacologia , Ácidos Prostanoicos/farmacologia , Tromboxano B2/metabolismoRESUMO
Radioimmunoassay (RIA) and high-resolution gas chromatography-mass spectrometry (HRGC-MS) were compared for the determination of serum 6-keto-PGF-1 alpha and TXB2 in a situation of drug-altered arachidonate metabolism. Results were comparable for TXB2 in both conditions. 6-keto-PGF1 alpha RIA determinations (with two different antisera) revealed increased levels in dazoxiben-treated samples, which were not confirmed by HRGC-MS. The assay were repeatedly checked in controlled conditions to investigate these discrepancies. Interference was found with both antisera, due to the drug-induced change in metabolism.
Assuntos
6-Cetoprostaglandina F1 alfa/sangue , Cromatografia Gasosa-Espectrometria de Massas , Oxirredutases/antagonistas & inibidores , Radioimunoensaio , Tromboxano B2/sangue , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxanos/sangue , Ácido Araquidônico , Ácidos Araquidônicos/sangue , Humanos , Imidazóis/farmacologia , Técnicas In VitroRESUMO
The development and biological application of a rapid method for quantitative profiling of prostaglandins and thromboxane using high-resolution gas chromatography (HRGC) coupled with mass spectrometry in the selected-ion monitoring technique (SIM) are described. The method is based on the single-step extraction of prostaglandins from biological samples on C18 reversed-phase cartridges after addition of deuterated analogues as internal standards, followed by derivatization of functional groups and final analysis by HRGC-SIM with wall-coated open tubular persilanized capillary columns. Biological applications include the determination of endogenous arachidonic acid cascade profiles in rat tissue homogenates and thromboxane synthetase inhibition studies in human serum.