thromboxane-a2 and carboprostacyclin

Atherosclerosis is a curious process of the intima of the vessel walls characterized by platelet aggregation, deposition of thrombotic material, lipid and fibrin which finally culminates in the intimal thickening, vascularization, and haemorrhage from the new vessels. The lipids demonstrated in the atherosclerotic plaque are mainly cholesterol, triglycerides, and phospholipids. Hyperlipidaemia initiates and maintains the atherosclerotic process and a diet rich in unsaturated essential fatty acids is known to be of benefit in arresting the process. Prostaglandins are formed from unsaturated essential fatty acids and are known to regulate platelet aggregation and thrombus formation. Thus atherosclerosis may be a disease of altered PG system and if so this would pave the way for new therapeutic strategies.

Topics: Alprostadil; Arteriosclerosis; Aspirin; Blood Vessels; Cell Membrane Permeability; Cell Survival; Cholesterol; Endothelium; Epoprostenol; Humans; Platelet Adhesiveness; Prostaglandins; Prostaglandins E; Thromboxane A2

To determine whether prostanoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and members of the tumor necrosis factor superfamily can regulate placental secretion of interleukin-6 (IL-6) and whether labor influences any such effects.. Villous fragments of term, human placenta were kept in culture for up to 4 hours, and IL-6 concentrations were measured in the supernatant. We assessed the effects of the following prostanoids: PGE(2), PGF(2alpha), thromboxane A(2) mimetic (U-46619), and carbacyclin, a stable prostacyclin analogue (all at 1 microM); NSAIDs: indomethacin (150 microM) or nimesulide (100 microM); and Fas ligand (5 ng/mL).. Secretion (mean +/- standard error) of IL-6 was, for control conditions, 1.92 +/- 0.28 fmol/mg wet weight per 3 hours; for PGE(2), 3.57 +/- 0.29 fmol/mg wet weight per 3 hours, P <.01; and for carbacyclin, 3.11 +/- 0.44 fmol/mg wet weight per 3 hours, P <.01. Incubation with PGF(2alpha) or the thromboxane A(2) analogue, U46619, had no effect on IL-6 secretion under these conditions. Fas ligand stimulated IL-6 secretion (3.06 +/- 0.38 fmol/mg wet weight per 3 hours, P <.05). Labor did not alter the effects of prostanoids or FasL. The effects of NSAIDs were assessed over 4 hours. Secretion (median, interquartile range) was, under control conditions 3.26, 2.83-6.23 fmol/mg wet weight per 4 hours, with indomethacin 1.4, 1.28-3.21 (P <.05), and with nimesulide 0.75, 0.50-1.56 fmol/mg wet weight per 4 hours. The magnitude of the effect of Fas ligand in the presence of NSAIDs depended on whether the placentas were delivered before or after labor.. Prostanoids, NSAIDs, and the Fas ligand regulate placental IL-6 secretion. Although the effects of individual agents did not vary with the presence or absence of labor, modulation of IL-6 secretion by labor became apparent when agents were combined.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anti-Inflammatory Agents, Non-Steroidal; Dinoprost; Dinoprostone; Drug Interactions; Epoprostenol; Fas Ligand Protein; Female; Humans; Interleukin-6; Labor, Obstetric; Membrane Glycoproteins; Models, Biological; Placenta; Pregnancy; Prostaglandins; Thromboxane A2; Tumor Necrosis Factor-alpha

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Chemotaxis; Dinoprost; Dinoprostone; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Unsaturated; Fibroblast Growth Factor 2; Humans; Hydrazines; Lung Neoplasms; Lymphokines; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Rats; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

This study was conducted to determine if high perinatal prostaglandin (PG) and thromboxane (TxA2) levels modified their choroidal vasomotor effects and receptor levels. Both nonperfused (eyecup preparations) and perfused choroidal vessels from saline- or ibuprofen-treated 1-day-old pigs and tissues from adult pigs were used; all prostanoids produced similar vasomotor effects on both preparations. Choroidal PGF2alpha, TxA2, PGI2, and PGD2 levels were higher in the newborn than in adult pigs; injections of ibuprofen (40 mg/kg every 4 h for 48 h) into newborn pigs significantly decreased choroidal levels of all these prostanoids. PGF2alpha and the TxA2 mimetic U-46619 caused less choroidal vasoconstriction and production of inositol 1,4,5-trisphosphate (IP3) in the newborn than in adult pigs. Ibuprofen treatment increased choroidal PGF2alpha vasoconstrictor effects, IP3 production, and receptors, but did not modify response to U-46619. Carbaprostacyclin (PGI2 analog) caused a greater choroidal vasodilatation and adenosine adenosine 3',5'-cyclic monophosphate (cAMP) production in the newborn than in adult pigs; these effects were not modified by ibuprofen. PGD2 did not increase cAMP but caused greater dilatation and nitrite [oxidation product of nitric oxide (NO)] production in the choroid of newborn than of adult pigs, which were decreased to adult levels by ibuprofen and the NO synthase inhibitor N(omega)-nitro-L-arginine. These data suggest that high perinatal PG levels downregulate PGF2alpha receptors and vascular effects but do not modify choroidal responses to TxA2 and PGI2; NO seems to contribute to the vasodilator effects of PGD2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aging; Animals; Animals, Newborn; Choroid; Cyclic AMP; Cyclic GMP; Dinoprost; Down-Regulation; Epoprostenol; Ibuprofen; Inositol 1,4,5-Trisphosphate; Nitric Oxide; Nitroarginine; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins, Synthetic; Receptors, Prostaglandin; Swine; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Arachidonic Acid; Blood Platelets; Chromatography, High Pressure Liquid; Collagen; Epoprostenol; Glutathione Transferase; GTP-Binding Proteins; Humans; Kinetics; Leukotriene C4; Platelet Membrane Glycoproteins; Prostaglandin Endoperoxides, Synthetic; Protein Kinase C; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Thrombin; Receptors, Thromboxane; Tetradecanoylphorbol Acetate; Thrombin; Thromboxane A2; Type C Phospholipases

This study tests the hypothesis that prostaglandins (PGs) released in response to phorbol esters act as modulators of the phorbol ester-induced smooth muscle contraction. The rate and magnitude of the phorbol 12-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin. The thromboxane (Tx) A2/PGH2 receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition was greater than that due to indomethacin. PMA induced the release of PGI2, PGE2, PGF2 alpha, and arachidonic acid, but not TxA2. The amount of PGI2 released was greater than that of PGE2 and PGF2 alpha. Indomethacin blocked the PMA-induced release of PG, but not of arachidonic acid. In PMA-contracted tissues, PGF2 alpha, PGE2, and the stable PGI2 and PGH2 analogues, carbacyclin and U-46619, respectively, induced further contraction. Pretreatment of PMA-contracted tissues with SQ-29548 partially inhibited the PGF2 alpha- and PGE2-induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These results demonstrate that, in rat aorta, PMA induces the release of PGs that exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-induced increase in PMA contraction is mediated, in large part, through TxA2/PGH2 receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA2/PGH2 receptor suggests that one or more of these PGs, in addition to, presumably, PGH2, may be responsible for the increase in PMA contraction. PGI2 is the only endogenously released PG that can account for the relaxant effect.

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Arachidonic Acid; Bridged Bicyclo Compounds, Heterocyclic; Epoprostenol; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Indomethacin; Kinetics; Male; Models, Cardiovascular; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins, Synthetic; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate; Thromboxane A2; Time Factors

Prostaglandin (PG) I2 elicits a biphasic concentration-response curve in rat aorta: lower concentrations elicit relaxation, whereas at higher concentrations, the relaxation is reversed. The purpose of this study was to investigate 1) the nature of the receptors that mediate these effects and 2) whether the relaxant efficacy of PGI2 is decreased at higher PGI2 concentrations by PGI2-induced contraction. PGI2 (1 microM), the stable PGI2 analogue carbacyclin (1 microM), and PGE1 (3 microM) induced maximal relaxations of 55, 40, and 63%, respectively, of norepinephrine-contracted aorta, whereas higher concentrations of PGI2, carbacyclin, and PGE1 reversed the relaxation. The thromboxane (Tx) A2-PGH2 receptor antagonist, SQ-29548, abolished the reversal of the PGI2-, carbacyclin-, and PGE1-induced relaxation, and maximal relaxations to PGI2, carbacyclin, and PGE1 increased to 73, 85, and 89% of the norepinephrine contraction, respectively, with 50% effective concentrations of 0.16, 0.43, and 0.83 microM, respectively. PGE2 and PGD2 did not induce relaxation in the presence or absence of SQ-29548. PGI2 and carbacyclin displaced the TxA2-PGH2 receptor ligand 1S-[1 alpha,2 beta(5Z),3 alpha(1E,3S),4 alpha]-7-(3-[3-hydroxy-4-(p- [125I]iodophenoxy)-1-butenyl]7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic acid from cultured rat aorta smooth muscle cells with concentrations of competing ligand that displaced 50% of the specifically bound radioligand from its binding site of 6.0 and 2.3 microM, respectively. These results suggest that 1) PGI2 induces relaxation through a PGI2-PGE1 receptor, and 2) higher concentrations of PGI2 act at the TxA2-PGH2 receptor to decrease PGI2-induced relaxation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Epoprostenol; Fatty Acids, Unsaturated; Hydrazines; Male; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasomotor System

FTIR spectra measurements and full optimization curve analysis of their spectra were done to obtain parameters of the OH and C = O stretching vibration bands for intramolecular hydrogen bondings in thromboxane (TX)A2 receptor partial agonist (CTA2), prostaglandin (PG)E2, PGD2, PGF2 alpha, prostacyclin (PGI2) receptor agonist (carbacyclin), and their related compounds in dilute CCl4 solutions. For CTA2, PGE2, PGD2, and PGF2 alpha, cyclic intramolecular hydrogen bonds involving a 15-membered ring similar to that observed for the TXA2 receptor agonist (U-46619) were found between a carboxyl group of the alpha-side chain and a 15-hydroxyl group of the omega-side chain. The arrangement of these side chains was P-shaped, and the percentage of the intramolecular hydrogen-bonded molecules with the 15-membered ring in CCl4 solution showed a high value of ca. 80% for these compounds. In addition, it was found that the cyclic intramolecular hydrogen bonds involving the 13-, 12-, and 12-membered rings in PGE2, PGD2, and PGF2 alpha, respectively, are formed between the carboxyl group of the alpha-side chain and the 11-, 9-, and 9-hydroxyl groups of a cyclopentane ring, respectively, although the percentages of the intramolecular hydrogen-bonded molecules with these membered rings are very small. It was also found that the hydrogen bond is more easily formed in the order of the 11-, 9-, and 15-hydroxyl groups. For carbacyclin, the cyclic intramolecular hydrogen bond involving the 13-membered ring was found between the carboxyl group of the alpha-side chain and the 11-hydroxyl group. The percentage of the intramolecular hydrogen-bonded molecules showed the value of 58% for carbacyclin. On the basis of information on the side-chain conformations in CCl4, we examined the structure-activity relationships for U-46619 in place of TXA2, PGE2, PGD2, PGF2 alpha, and carbacyclin in place of PGI2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds; Carbon Tetrachloride; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Fatty Acids, Monounsaturated; Hydrogen Bonding; Macromolecular Substances; Models, Molecular; Molecular Structure; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Solutions; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Thromboxane A2

Subarachnoid hemorrhage (SAH) was induced in 50 rabbits by injecting 1.25 cc/kg of autologous, well heparinized, fresh arterial blood into the cisterna magna, followed by suspending the animals in a head-down position at 30 degrees for 15 minutes. The animals were evenly divided into five groups: a control group, or groups receiving post-SAH prostacyclin (PGI2), carbacyclin, thromboxane A2 (TXA2) synthetase inhibitor (OKY-1581), or nutralipid. Radiographic vertebrobasilar arterial spasm was demonstrated on the 3rd day post-SAH in the control animals. This was decreased in the prostacyclin and the carbacyclin groups and was absent in the OKY-1581 and the nutralipid groups. Cerebral blood flow (CBF) measurements on the 4th day post-SAH using the xenon-133 technique failed to reveal any significant difference between the prostacyclin, the carbacyclin, and the control groups, but flows in the nutralipid and the OKY-1581 groups were significantly higher. There was a good correlation between the clinical status and the CBF. Intracytoplasmic vacuolation and detachment of the vascular endothelium, seen ultrastructurally, may account for the impaired synthesis of prostacyclin. Exogenous prostacyclin and carbacyclin decreased vasospasm but failed to improve cerebral perfusion. OKY-1581 blocked the synthesis of the potent vasoconstrictor, TXA2, which is not only formed during platelet aggregation but also induces platelet aggregation. Nutralipid contains linolenic acid, a precursor of eicosapentaenoic acid (EPA), which is more potent in inhibiting platelet aggregation and in blocking TXA2 production. The various fatty acid constituents of nutralipid bind to albumin and thereby shorten the half-life of TXA2.

Topics: Acrylates; Animals; Cerebrovascular Circulation; Epoprostenol; Fatty Acids; Female; Ischemic Attack, Transient; Male; Methacrylates; Rabbits; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane-A Synthase