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At least 19 recordsLinked to original sources
PubMed1990

Stabilization of prostaglandin synthetase by immobilization of goat seminal microsomes on silica gel-G.

Prostaglandin synthetase was immobilized by adsorption of goat vesicular microsomes on silica gel containing CaSO4 (silica gel G). Repeated cycles of enzymatic conversion of arachidonic acid to prostaglandin by the immobilized microsomes increased the product yield by 1.5 fold, in comparison to the same by free microsomal particles. The presence of Ca2+ in silica gel is responsible for this improved yield of prostaglandin as the divalent metal ion stabilized prostaglandin synthetase activity in a remarkable way. Microsomal particles immobilized on solid supports like alumina G and controlled pore glass were not very effective.

Animals↗
PubMed1977

Stimulation of prostaglandin biosynthesis by lipoic acid.

Enzyme preparations from sheep seminal vesicles display an enhanced ability to synthesize prostaglandins, particularly prostaglandin F from polyunsaturated fatty acids if alpha-lipoic acid is present in the incubation mixture prior to the addition of fatty acid. The stimulation by lipoate is reversible, time dependent, and involves modifications of V and Km for oxygenase activity. Product studies, structure vs. activity studies, and purification data indicate that lipoate exerts it effect by a mechanism distinct from a glutathione-like metabolism of the endoperoxide linkage in prostaglandin G and prostaglandin H. In addition, product studies suggest that lipoate is not a cofactor for the endoperoxide isomerase component of prostaglandin synthetase. Purification of the endoperoxide synthesizing activity by ion-exchange chromatography and isoelectric focusing yields preparations which are more responsive to lipoate than microsomal preparations.

Animals↗
PubMed1975

On agents favoring prostaglandin f formation during biosynthesis.

The microsomal fraction of bovine vesicular gland catalyzed the conversion of eicosapolyenoic acids exclusively to prostaglandin E in the presence of reduced glutathione, while hydrox fatty acids, prostaglandins D and F, decreased to a negligible level. After solubilizing the microsomal fraction with cutscum, the prostaglandin synthetase activity was purified 11-fold by batchwise absorption and elution of the enzyme activity from DEAE-cellulose. This partially purified enzyme fraction did not respond to reduced glutathione in promoting prostaglandin E formation at the expense of other products. A number of glutathione analogs were examined, but none of these was as effective as reduced glutathione. Dithiol complexes of Cu-2+, Ni-2+, and Zn-2+ exerted pronounced effects on relative amounts of the different prostaglandins biosynthesized. Both the Cu-2+-dithiothreitol (2:1) complex and stannous chloride markedly enhanced prostaglandin F synthesis at the expense of prostaglandin D and prostaglandin E. The following reagents chemically reduced the endoperoxide in ascaridole to p-menth-2-ene-cis-1,4-diol: Cu-2+0dithiothreitol, Cu-2+-epinephrine, and stannous chloride. It is concluded that the enhancement of prostaglandin F formation caused by copper-dithiols and L-epinephrine is due to nonenzymatic reduction of prostaglandin G or prostaglandin H.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1987

Glycogenolytic and haemodynamic responses to heat-aggregated immunoglobulin G and prostaglandin E2 in the perfused rat liver.

Infusion of heat-aggregated immunoglobulin G (HAG) into perfused livers from fed rats caused transient increases in hepatic glycogenolysis and portal-vein pressure, accompanied by a transient increase in hepatic glycogen phosphorylase alpha content. The hepatic responses to HAG were inhibited by indomethacin (2 microM). In contrast, HAG was without effect on phosphorylase alpha content and glucose output in isolated hepatocytes. HAG infusion caused a transient decrease in hepatic cyclic AMP. Lowering the extracellular Ca2+ concentration to 6 or 50 microM attenuated markedly the glycogenolytic and haemodynamic responses to HAG; efflux of Ca2+ from the liver was not observed in response to HAG. Co-infusion of the specific platelet-activating-factor antagonist U-66985 (1-O-octadecyl-2-O-acetyl-sn-glycero-3-phosphoric acid 6'-trimethylammoniumhexyl ester) did not attenuate the glycogenolytic response to HAG. Infusion of prostaglandin E2 caused increases in glucose output, portal-vein pressure and the reduction state of the cytosolic NAD(H) redox couple similar to those seen with HAG. The present study suggests that the glycogenolytic activation after HAG infusion may be an indirect consequence of the haemodynamic response of the hepatic vasculature to stimulation of the reticuloendothelial cells of the liver.

Animals↗
PubMed1974

Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation.

Incubation for a short time of arachidonic acid with the microsomal fraction of a homogenate of the vesicular gland of sheep in the presence of 1 mM p-mercuribenzoate followed by extraction and silicic acid chromatography yielded two prostaglandin endoperoxides. The structures of these compounds, i.e., 15-hydroperoxy-9alpha,11alpha-peroxidoprosta-5,13-dienoic acid (prostaglandin G(2)) and 15-hydroxy-9alpha,11alpha-peroxidoprosta-5,13-dienoic acid (prostaglandin H(2)), were assigned mainly by a number of chemical transformations into previously known prostaglandins. The new prostaglandins were 50-200 times (prostaglandin G(2)) and 100-450 times (prostaglandin H(2)) more active than prostaglandin E(2) on the superfused aorta strip. The half-life of the prostaglandin endoperoxides in aqueous medium (about 5 min) was significantly longer than that of "rabbit aorta-contracting substance" released from guinea pig lung, indicating that none of the prostaglandin endoperoxides is identical with this factor. Addition of 10-300 ng/ml of the endoperoxides to suspensions of washed human platelets resulted in rapid aggregation. Furthermore, platelet aggregation induced by thrombin was accompanied by release of material reducible by stannous chloride into prostaglandin F(2alpha), thus indicating the involvement of endogenous prostaglandin endoperoxides in platelet aggregation.

Animals↗
PubMed1980

Cerebral arteriolar damage by arachidonic acid and prostaglandin G2.

Application of arachidonic acid or prostaglandin G(2) to the brain surface of anesthetized cats induced cerebral arteriolar damage. Scavengers of free oxygen radicals inhibited this damage. Prostaglandin H(2), prostaglandin E(2), and 11,14,17-eicosatrienoic acid did not produce arteriolar damage. It appears that increased prostaglandin synthesis produces cerebral vascular damage by generating free oxygen radicals.

Animals↗
PubMed1999

The binding of arachidonic acid in the cyclooxygenase active site of mouse prostaglandin endoperoxide synthase-2 (COX-2). A putative L-shaped binding conformation utilizing the top channel region.

The chemical mandates for arachidonic acid conversion to prostaglandin G(2) within the cyclooxygenase (COX) active site predict that the substrate will orient in a kinked or L-shaped conformation. Molecular modeling of arachidonic acid in sheep COX-1 confirms that this L-shaped conformation is possible, with the carboxylate moiety binding to Arg-120 and the omega-end positioned above Ser-530 in a region termed the top channel. Mutations of Gly-533 to valine or leucine in the top channel of mCOX-2 abolished the conversion of arachidonic acid to prostaglandin G(2), presumably because of a steric clash between the omega-end of the substrate and the introduced side chains. A smaller G533A mutant retained partial COX activity. The loss of COX activity with these mutants was not the result of reduced peroxidase activity, because the activity of all mutants was equivalent to the wild-type enzyme and the addition of exogenous peroxide did not restore full COX activity to any of the mutants. However, the Gly-533 mutants were able to oxidize the carbon 18 fatty acid substrates linolenic acid and stearidonic acid, which contain an allylic carbon at the omega-5 position. In contrast, linoleic acid, which is like arachidonic acid in that its most omega-proximal allylic carbon is at the omega-8 position, was not oxidized by the Gly-533 mutants. Finally, the ability of Gly-533 mutants to efficiently process omega-5 allylic substrates suggests that the top channel does not serve as a product exit route indicating that oxygenated substrate diffuses from the cyclooxygenase active site in a membrane proximal direction.

Animals↗
PubMed2000

Different catalytically competent arrangements of arachidonic acid within the cyclooxygenase active site of prostaglandin endoperoxide H synthase-1 lead to the formation of different oxygenated products.

Arachidonic acid is converted to prostaglandin G(2) (PGG(2)) by the cyclooxygenase activities of prostaglandin endoperoxide H synthases (PGHSs) 1 and 2. The initial, rate-limiting step is abstraction of the 13-proS hydrogen from arachidonate which, for PGG(2) formation, is followed by insertion of O(2) at C-11, cyclization, and a second O( 2) insertion at C-15. As an accompaniment to ongoing structural studies designed to determine the orientation of arachidonate in the cyclooxygenase site, we analyzed the products formed from arachidonate by (a) solubilized, partially purified ovine (o) PGHS-1; (b) membrane-associated, recombinant oPGHS-1; and (c) a membrane-associated, recombinant active site mutant (V349L oPGHS-1) and determined kinetic values for formation of each product. Native forms of oPGHS-1 produced primarily PGG(2) but also several monohydroxy acids, which, in order of abundance, were 11R-hydroxy-5Z, 8Z,12E,14Z-eicosatetraenoic acid (11R-HETE), 15S-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid (15S-HETE), and 15R-HETE. V349L oPGHS-1 formed primarily PGG(2), 15S-HETE, and 15R-HETE but only trace amounts of 11R-HETE. With native enzyme, the K(m) values for PGG(2), 11-HETE, and 15-HETE formation were each different (5.5, 12.1, and 19.4 microM, respectively); similarly, the K(m) values for PGG(2) and 15-HETE formation by V349L oPGHS-1 were different (11 and 5 microM, respectively). These results establish that arachidonate can assume at least three catalytically productive arrangements within the cyclooxygenase site of oPGHS-1 leading to PGG(2), 11R-HETE, and 15S-HETE and/or 15R-HETE, respectively. IC(50) values for inhibition of formation of the individual products by the competitive inhibitor, ibuprofen, were determined and found to be the same for a given enzyme form (i.e. 175 microM for oPGHS-1 and 15 microM for V349L oPGHS-1). These latter results are most simply rationalized by a kinetic model in which arachidonate forms various catalytically competent arrangements only after entering the cyclooxygenase active site.

Animals↗
PubMed2001

The cyclooxygenase hydroperoxide product PGG(2) activates synaptic nitric oxide synthase: a possible antioxidant response to membrane lipid peroxidation.

Nitric oxide is a potent inhibitor of membrane lipid peroxidation. It is unknown, however, whether nitric oxide synthase (NOS) activity increases under conditions of membrane lipid peroxidation. Importantly, cyclooxygenase (COX)-catalyzed peroxidation of arachidonic acid is well-established to be increased by lipid hydroperoxides. The results of the present study demonstrate that the COX hydroperoxide product prostaglandin G(2) (PGG(2)) greatly stimulated NOS activity in synaptosomal membrane fractions from rat brain in a dose-dependent (EC(50) = 0.2 microM) manner in the presence of ATP and the antioxidant urate. NOS activation was also produced, albeit to a lesser extent, by 15-hydroperoxyeicosatetraenoic acid (15-HPETE) but not by the corresponding hydroxy compounds PGH(2) and 15-HETE or by hydrogen peroxide. These findings demonstrate that PGG(2)-activated synaptic NOS by a hydroperoxide-mediated pathway and support the view that NOS activation may be an important physiological response to lipid peroxidation.

Animals↗
PubMed2000

Interactions of nitric oxide with lipid peroxidation products under aerobic conditions: inhibitory effects on the formation of malondialdehyde and related thiobarbituric acid-reactive substances.

Under aerobic conditions, exposure of peroxidized lipids to nitric oxide (NO) was found to result in a rapid decrease in the levels of thiobarbituric acid-reactive substances (TBARS). Addition of 10-100 microM NO to rat brain homogenates preincubated for 2 h at 37 degrees C caused up to a 20% decrease in the levels of TBARS compared to controls. A similar inhibitory effect was observed on TBARS produced by Fe(2+)-induced decomposition of 15-hydroperoxyeicosatetraenoic acid (15-HPETE), due apparently to NO-induced decomposition of the hydroperoxide (ferrous oxidation/xylenol orange assay). Prostaglandin G(2) (PGG(2), 35 microM), as a model bicyclic endoperoxide, and malondialdehyde (MDA, 20 microM), the main component of TBARS, proved also susceptible to degradation by NO or NO donors (diethylamine NONOate, DEA/NO) at concentrations of 100 microM or higher in 0.05 M phosphate buffer, pH 7.4, and at 37 degrees C, as indicated by the reduced response to the TBA assay. No significant effect on TBARS determination was caused by nitrite ions. These and other data indicate that NO can inhibit TBARS formation by decomposing primary lipid peroxidation products, chiefly 15-HPETE and related hydroperoxides, and, to a lesser extent, later stage TBARS precursors, including bicyclic endoperoxides and MDA, via nitrosation and other oxidative routes, without however affecting chromogenic reactions during the assay.

Animals↗
PubMed2002

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases.

Acetaminophen has antipyretic and analgesic properties yet differs from the nonsteroidal antiinflammatory drugs and inhibitors of prostaglandin H synthase (PGHS)-2 by exhibiting little effect on platelets or inflammation. We find parallel selectivity at a cellular level; acetaminophen inhibits PGHS activity with an IC(50) of 4.3 microM in interleukin (IL)-1 alpha-stimulated human umbilical vein endothelial cells, in contrast with an IC(50) of 1,870 microM for the platelet, with 2 microM arachidonic acid as substrate. This difference is not caused by isoform selectivity, because acetaminophen inhibits purified ovine PGHS-1 and murine recombinant PGHS-2 equally. We explored the hypothesis that this difference in cellular responsiveness results from antagonism of the reductant action of acetaminophen on the PGHSs by cellular peroxides. Increasing the peroxide product of the PGHS-cyclooxygenase, prostaglandin G(2) (PGG(2)), by elevating the concentration of either enzyme or substrate reverses the inhibitory action of acetaminophen, as does the addition of PGG(2) itself. 12-Hydroperoxyeicosatetraenoic acid (0.3 microM), a major product of the platelet, completely reverses the action of acetaminophen on PGHS-1. Inhibition of PGHS activity by acetaminophen in human umbilical vein endothelial cells is abrogated by t-butyl hydroperoxide. Together these findings support the hypothesis that the clinical action of acetaminophen is mediated by inhibition of PGHS activity, and that hydroperoxide concentration contributes to its cellular selectivity.

6-Ketoprostaglandin F1 alpha↗
PubMed1977

Prostaglandin endoperoxide E isomerase from bovine vesicular gland microsomes, a glutathione-requiring enzyme.

Prostaglandin endoperoxide E isomerase catalyzes the isomerization of the endoperoxy group of prostaglandin H and produces prostaglandin E. The enzyme was solubilized with Tween 20 from bovine vesicular gland microsomes and purified 26-fold by successive column chromatography on DEAE-cellulose and omega-aminobutyl Sepharose 4B. The previously known requirement for glutathione was further investigated. The activity of freshly prepared enzyme was destroyed rapidly with a half-life of about 30 min at 24 degrees, pH 8.0. Various thiol compounds including glutathione protected the enzyme from such an inactivation. However, several findings indicated that glutathione was possibly specifically involved as a coenzyme in the isomerase reaction, but was not oxidized in a stoichiometric quantity. The enzyme also isomerized prostaglandin G at a rate approximately half of that of prostaglandin H.

Animals↗
PubMed1999

Distinct roles of prostaglandin H synthases 1 and 2 in T-cell development.

Prostaglandin G and H synthases, or cyclooxygenases (COXs), catalyze the formation of prostaglandins (PGs). Whereas COX-1 is diffusely expressed in lymphoid cells in embryonic day 15.5 thymus, COX-2 expression is sparse, apparently limited to stromal cells. By contrast, COX-2 is predominant in a subset of medullary stromal cells in three- to five-week-old mice. The isozymes also differ in their contributions to lymphocyte development. Thus, experiments with selective COX-1 inhibitors in thymic lobes from normal and recombinase-activating gene-1 knockout mice support a role for this isoform in the transition from CD4(-)CD8(-) double-negative (DN) to CD4(+)CD8(+) double-positive (DP). Concordant data were obtained in COX-1 knockouts. Pharmacological inhibition and genetic deletion of COX-2, by contrast, support its role during early thymocyte proliferation and differentiation and, later, during maturation of the CD4 helper T-cell lineage. PGE2, but not other PGs, can rescue the effects of inhibition of either isoform, although it acts through distinct EP receptor subtypes. COX-dependent PG generation may represent a mechanism of thymic stromal support for T-cell development.

Animals↗
PubMed1996

Comparative Effects of N(omega)-L-Nitro-L-Arginine Methyl Ester and N(omega)-L-Nitro-L-Arginine Benzyl Ester in the Mesenteric Circulation of the Rat.

Comparative effects of the nitric oxide (NO) synthase inhibitors, N(omega)-L-nitro-L-arginine methyl ester, and N(omega)-L-nitro-L-arginine benzyl ester on baseline arterial tone and on vasodilator responses to acetylcholine, isoproterenol, prostaglandin E(1), histamine, and nitroglycerin were investigated in the isolated mesenteric vascular bed of the rat. Under constant-flow conditions, intra-arterial (IA) injections of acetylcholine (100 ng--1 &mgr;g), isoproterenol (100 ng--1 &mgr;g), prostaglandin E(1) (0.3--3 &mgr;g), histamine (300 ng--3 &mgr;g), and nitroglycerin (100 ng--1 &mgr;g) caused dose-related decreases in mesenteric arterial perfusion pressure and decreases in systemic arterial pressure. Following administration of the NO synthase inhibitors, N(omega)-L-nitro-L-arginine methyl ester or N(omega)-L-nitro-L-arginine benzyl ester, mesenteric vascular resistance, and systemic arterial pressure were increased and mesenteric vasodilator responses to acetylcholine were significantly decreased, whereas N(omega)-L-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine benzyl ester did not significantly decrease vasodilator responses to nitroglycerin, histamine, isoproterenol, or prostaglandin E(1). The inhibitory effects of N(omega)-L-nitro-L-arginine methyl ester and N(omega)-L-nitro-L-arginine benzyl ester on vasodilator responses to acetylcholine suggest that acetylcholine-induced vasodilation in the mesenteric circulation of the rat is dependent on the release of NO from the endothelium. The increase in mesenteric vascular resistance following administration of N(omega)-L-nitro-L-arginine methyl ester and N(omega)-L-nitro-L-arginine benzyl ester suggest that tonic production of NO by the endothelium serves to maintain the mesenteric vascular bed of the rat in a dilated state.

Journal Article↗
PubMed1975

Effect of PGF2alpha in pseudopregnancy.

Eleven normal female volunteers received human chorionic gonadotropin (HCG) intramuscularly to induce a pseudopregnant state. Twenty-five milligrams of prostaglandin F2alpha (PGF2alpha) was administered intravenously at selected times during the luteal phase to demonstrate a luteolytic effect, or a local effect upon the endometrium producing early vaginal bleeding. Careful comparison of hormone levels and clinical details in these cycles showed that a) 1000 IU HCG daily does not consistently prolong the luteal phase; b) 2500 IU HCG daily does significantly prolong the luteal phase; c) HCG administration significantly increases progesterone and estradiol output in the treated luteal phase; d) prostaglandin administration at selected times during the luteal phase does not consistently decrease estradiol or progesterone output from the corpus luteum or induce early vaginal bleeding; e) prostaglandin F2alpha, a known stimulant of uterine contractility probably causes vaginal bleeding by mechanical means, as evidenced by show of menses in patients with progesterone levels elevated above normal; f) although variations in progesterone and estradiol output occurred during the hours of prostaglandin infusion, no consistent change was observed except for a compensatory rebound in progesterone output; g) prostaglandin F2alpha, in the dose utilized, is not a luteolytic agent.

Adult↗
PubMed2000

Stereospecificity of hydrogen abstraction in the conversion of arachidonic acid to 15R-HETE by aspirin-treated cyclooxygenase-2. Implications for the alignment of substrate in the active site.

The initial and rate-limiting step in prostaglandin biosynthesis is stereoselective removal of the pro-S hydrogen from the 13-carbon of arachidonic acid. This is followed by oxygenation at C-11, formation of the five-membered ring, and a second oxygenation at C-15 to yield the endoperoxide product, prostaglandin G(2). Aspirin treatment of cyclooxygenase-2 is known to acetylate an active site serine, block prostaglandin biosynthesis, and give 15R-hydroxyeicosatetraenoic acid (15R-HETE) as the only product. 15R-HETE and prostaglandins have opposite stereoconfigurations of the 15-hydroxyl. To understand the changes that lead to 15R-HETE synthesis in aspirin-treated COX-2, we employed pro-R- and pro-S-labeled [13-(3)H]arachidonic acids to investigate the selectivity of the initial hydrogen abstraction. Remarkably, aspirin-treated COX-2 formed 15R-HETE with removal of the pro-S hydrogen at C-13 (3-9% retention of pro-S tritium label), the same stereoselectivity as in the formation of prostaglandins by native cyclooxygenase. To account for this result and the change in oxygenase specificity, we suggest that the bulky serine acetyl group forces a realignment of the omega end of the arachidonic acid carbon chain. This can rationalize abstraction of the C-13 pro-S hydrogen, the blocking of prostaglandin synthesis, and the formation of 15R-HETE as the sole enzymatic product.

Acetylation↗
PubMed1979

Effects of prostaglandin cyclic endoperoxides on the lung circulation of unanesthetized sheep.

Although prostaglandins E(2) and F(2alpha) have been suggested as mediators of the pulmonary hypertension seen after endotoxin infusion or during alveolar hypoxia, their precursors, the endoperoxides (prostaglandins G(2) and H(2)) are much more potent vasoconstrictors in vitro. In this study we compared the effects of prostaglandin (PG)H(2), a stable 9-methylene ether analogue of PGH(2) (PGH(2)-A), PGE(2), and PGF(2alpha) on pulmonary hemodynamics in awake sheep. The animals were prepared to allow for measurement of (a) lung lymph flow; (b) plasma and lymph protein concentration; (c) systemic and pulmonary vascular pressures; and (d) cardiac output. We also determined the effect of prolonged PGH(2)-A infusions on lung fluid balance and vascular permeability by indicator dilution methods, and by assessing the response of lung lymph. Both PGH(2) and PGH(2)-A caused a dose-related increase in pulmonary artery pressure: 0.25 mug/kg x min tripled pulmonary vascular resistance without substantially affecting systemic pressures. Both were 100 times more potent than PGE(2) or PGF(2alpha) in this preparation. PGH(2)-A, as our analysis of lung lymph and indicator dilution measurements show, does not increase the permeability of exchanging vessels in the lung to fluid and protein. It does, however, augment lung fluid transport by increasing hydrostatic pressure in the pulmonary circulation. We conclude: (a) that PGH(2) is likely to be an important mediator of pulmonary vasoconstriction; (b) its effects are probably not a result of its metabolites PGE(2) or PGF(2alpha).

Animals↗