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At least 163 records · Page 9Linked to original sources
PubMed1984

Arachidonic acid-induced platelet aggregation is mediated by a thromboxane A2/prostaglandin H2 receptor interaction.

The mechanism by which the active metabolites of arachidonic acid (AA), i.e., thromboxane A2 and/or prostaglandin H2 (TXA2/PGH2) induce platelet aggregation is not understood. Several reports have suggested that AA-stimulated aggregation is mediated by secreted ADP, whereas other studies have proposed that this response is ADP-independent. In the present report, we used the specific TXA2/PGH2 receptor antagonist, 13-azaprostanoic acid (13-APA), and the ADP antagonist, ATP, to examine the contribution of TXA2/PGH2 or secreted ADP to aggregation. We found that 13-APA, but not ATP, deaggregates platelets stimulated by AA or U46619 (a TXA2/PGH2 mimetic). In contrast, ADP-induced aggregation was reversed in response to ATP but not to 13-APA. These results suggest that TXA2/PGH2-stimulated aggregation is mediated through TXA2/PGH2 receptor occupation. Furthermore, secreted ADP does not appear to be required for maintenance of the AA-aggregation response.

Adenosine Diphosphate↗
PubMed1985

Thromboxane A2/prostaglandin H2 mobilizes calcium in human blood platelets.

The present study investigated the mechanism by which thromboxane A2/prostaglandin H2 (TXA2/PGH2) stimulates platelet activation. Previous studies in isolated platelet vesicles have suggested that TXA2/PGH2 functions to release calcium from intraplatelet stores. On this basis, we investigated whether TXA2/PGH2 causes mobilization of calcium in intact platelets. Calcium redistribution was measured using the fluorescent probe, chlortetracycline (CTC), and a photon-counting microspectrofluorometer. Human platelet-rich plasma was incubated with CTC (50 microM) for 40 min at 25 degrees C. Shape change was induced with arachidonic acid (AA, 100 microM) or ADP (0.75-1.0 microM). It was found that AA addition resulted in a significant release of intraplatelet calcium. This release was blocked by inhibition of the cyclooxygenase with indomethacin (20 microM) or the specific TXA2/PGH2 antagonist, 13-azaprostanoic acid (13-APA, 100 microM). On the other hand, neither indomethacin nor 13-APA had any effect on calcium release stimulated by ADP. However, prostacyclin (13 nM) inhibited both AA- and ADP-induced calcium release. These findings provide evidence that cyclooxygenase products of AA, i.e., TXA2 and/or PGH2 directly caused the mobilization of intraplatelet calcium. Furthermore, this calcium mobilization appears to be mediated through a specific TXA2/PGH2 receptor interaction.

Adenosine Diphosphate↗
PubMed1986

[The significance of eicosanoids in glomerular diseases].

Prostanoids are local cyclooxygenase products, synthesized by mesangial and epithelial cells of the glomerulus as well as by a variety of inflammatory cells and platelets. Prostaglandins and thromboxane have direct vasodilatory and vasoconstrictory effects and can modulate glomerular function. Arachidonic acid, the main substrate for cyclooxygenase, can also be metabolized by the lipoxygenase pathway to leukotrienes, substances which are primarily synthesized in inflammatory cells. In several models induction of immunologic glomerular injury is associated with an increased glomerular formation of cyclooxygenase and lipoxygenase products. The changes in cyclooxygenase products have been shown to account for some hemodynamic changes found in some of these models. Increased renal prostanoid formation is also present in patients with glomerular disease. There is some evidence that increased renal PG-formation in patients with moderate glomerular disease regulates GFR and mediates proteinurie in some of these patients. Leukotrienes are chemotactive substances which modulate the function of inflammatory cells, stimulate the growth of mesangial cells, and constrict mesangial cells in culture. Thus, these compounds might be mediators in the induction of immune mediated glomerular disease.

Animals↗
PubMed2001

A functional study on prostanoid receptors involved in cultured human iridal melanocyte stimulation.

The effects of various prostanoids on the growth, melanogenesis and dendrification of cultured iridal melanocytes were studied. Iridal melanocytes were isolated and cultured with medium supplemented with cAMP elevating agents and basic fibroblast growth factor (bFGF) (complete medium). The iridal melanocytes were plated into multiple well plates and cultured with complete medium or various deleted media with or without various prostanoids at different concentrations. After 6 days, the numbers of cells and dendrites were counted and melanin content was measured and compared with controls. Prostaglandin E(2), an EP(2)receptor agonist (AH 13205) and AGN 192093 (thromboxane mimetic) stimulated growth, melanogenesis and dendrification of cultured iridal melanocytes in cAMP-deleted medium. A mixed EP(1)and EP(3)receptor agonist (sulprostone), a EP(4)receptor agonist (ONO-AE1-329), IP receptor agonists (cicaprost or iloprost) and a TP receptor agonist (U-46619) showed no effect. Prostaglandin D(2)showed stimulating effects. However, these stimulating effects could not be blocked by the addition of a DP receptor antagonist (BW A868C). Furthermore, a DP receptor agonist (BW 245C) showed no effects, indicating that the effect of prostaglandin D(2)may involve receptors other than the DP receptor subtype. The present study indicates that: (1) among various EP receptor agonists, only an EP(2)receptor agonist has stimulating effects on iridal melanocytes; (2) DP, IP and TP receptor agonists do not have stimulating effects; and (3) the mechanisms of action of prostaglandin D(2)and AGN 192093 need further study.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Differences between in vivo and in vitro production of eicosanoids following long-term dietary fish oil supplementation in the rat.

The effects of different lipid supplements on endogenous and exogenous production of eicosanoids were investigated in the rat following a 12-month pre-feeding period. The urinary excretion of tetranorprostanemonoic (TPM) and tetranorprostanedioic (TPD) acids was measured as an index of endogenous production whilst myocardial release of PGI2 and TXA2 was estimated under in vitro conditions. Compared to the reference group, n-3 PUFA rich tuna fish oil (TFO) fed rats displayed a near doubling of endogenous (TPM + TPD) synthesis; however, myocardial production was reduced by 32% (PGI2) and 55% (TXA2). Sheep fat supplementation also caused a 62% rise in urinary tetranor metabolites but in contrast to TFO feeding, myocardial production in vitro also showed a significant increase (P less than 0.05). Considerable changes in PUFA profile of plasma, heart and kidney occurred as a result of dietary lipid treatment and in addition a high tissue specificity was also noted with regard to the incorporation and conversion of dietary n-3 PUFA. For example, the heart showed a low EPA (1.2%) and high DHA (28.0%), whereas their proportions in the kidney were near equal (6-7%). As only the TFO diet exerted a significant effect on the proportion of AA, the changes in eicosanoid production cannot be fully explained on the basis of precursor/inhibitor availability. The results probably reflect the complex interactions between fatty acid substrates, release mechanisms and biosynthetic enzymes.

Animals↗
PubMed1985

Reversal of thromboxane A2/prostaglandin H2 and ADP-induced calcium release in intact platelets.

We previously demonstrated that thromboxane A2 and/or prostaglandin H2 (TXA2/PGH2), ADP, and A23187 cause calcium mobilization in intact human platelets. Other studies have also shown that platelet shape change and aggregation induced by a variety of platelet agonists can be reversed by specific antagonists. In the present study, we used the fluorescent calcium probe chlortetracycline to evaluate whether the reversal of platelet activation involves a resequestration of intraplatelet calcium. It was found that the TXA2/PGH2 receptor antagonist 13-azaprostanoic acid (13-APA) reversed calcium mobilization and shape change induced by AA but not that induced by ADP. A similar specificity of action was observed using the specific ADP receptor antagonist, ATP, in that ATP only reversed ADP-induced calcium release and shape change. In contrast, prostacyclin reversed both AA and ADP-induced calcium redistribution and shape change. In the latter experiments, a net calcium sequestration was actually observed on prostacyclin addition. These findings indicate that the resequestration of released calcium leads to platelet deactivation. Furthermore, there appear to be at least two mechanisms by which a reduction in cytosolic calcium can be produced: specific interruption of the agonist-receptor interaction, for example, 13-APA antagonism of TXA2/PGH2; and stimulation of platelet adenosine 3',5'-cyclic monophosphate production by prostacyclin and consequent calcium sequestration.

Adenosine Diphosphate↗
PubMed2000

Adrenaline potentiates type 2B von Willebrand factor-induced activation of human platelets by enhancing both the formation and action of thromboxanes.

Von Willebrand factor (vWF) is a large plasma glycoprotein that mediates platelet adhesion at sites of vascular injury. We have previously reported that the pathological type 2B (formerly named type IIB) variant of vWF promotes platelet activation through phospholipase A(2)-mediated release of arachidonic acid. The present report shows that adrenaline (1 microM) potentiates type 2B vWF-induced platelet aggregation, serotonin secretion, rise in cytosolic Ca(2+) concentration, and pleckstrin phosphorylation, as well as thromboxane B(2) production. The hormone also increases the partially inhibited release of serotonin observed in platelets pretreated with the anti-GPIIb-IIIa antibody LJCP8 but does remove the total inhibition on the secretion caused by the anti-GPIb antibody LJIB1. Adrenaline also increases type 2B vWF-elicited tyrosine phosphorylation of proteins with apparent molecular masses of 60 and 80 kDa. Furthermore, adrenaline potentiates the rise in cytosolic Ca(2+) and the release of thromboxane B(2) in platelets stimulated with arachidonic acid (2 microM) as well as the increase in Ca(2+) induced by the thromboxane mimetic U46619 (0.3 microM). Platelet pretreatment with yohimbine or 13-azaprostanoic acid, which are antagonists of the alpha(2)-adrenergic and thromboxane receptors, respectively, or with acetylsalicylate and indomethacin, both of which act as inhibitors of thromboxane formation, abolishes the potentiating effect of adrenaline. These observations lead to the conclusion that the potentiating action of adrenaline on type 2B vWF-promoted platelet responses is due to an increase in both the formation and activating action of thromboxanes.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

Antagonism of prostanoid-induced vascular contraction by 13-azaprostanoic acid (13-APA).

Isometric contractions in vitro of helically cut strips of canine mesenteric arteries (O.D. = 0.6-1 mm) were recorded in the presence of 10 microM indomethacin. PGF2 alpha PGE2, U-46619 (TXA2 mimetic), norepinephrine, 5-hydroxytryptamine, and KCl produced dose-related contractions. The EC50 values of the prostanoids in the control period were: PGF2 alpha, 7.3 +/- 0.7 X 10(-7) M; PGE2, 2.1 +/- 0.2 X 10(-6) M; and U-46619, 4.1 +/- 1.0 X 10(-10) M. Exposure to 13-azaprostanoic acid (13-APA), 5 X 10(-5) M and 2 X 10(-4) M, for 20 min caused parallel and dose-related shifts to the right of the dose-response curves generated by all three prostanoids without affecting the contractile responses to KCl, norepinephrine, or 5-hydroxytryptamine or relaxation induced by PGI2. 13-APA, at the concentrations used, had no agonist activity. Small contractions (10-15%) seen on the addition of 13-APA to the baths were found to be related to the alcohol content of the solvent. Dose ratios (with/without antagonist) at the EC50 level were found to be: in the presence of 5 X 10(-5) M 13-APA PGF2 alpha, 2.7 +/- 0.3; PGE2, 3.5 +/- 0.9; U-46619, 5.2 +/- 0.9; in the presence of 2 X 10(-4) M 13-APA PGF2 alpha, 17.1 +/- 3; PGE2, greater than 50; and U-46619, 23.3 +/- 5.7. Thus, 13-APA is a specific antagonist of these prostanoids with no agonist activity of its own.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1985

Acetyl glycerylphosphorylcholine aggregates human platelets through two distinct pathways, both dependent on arachidonic acid metabolism.

Acetyl glyceryl ether phosphorylcholine (AGEPC) is a mediator of inflammation and anaphylaxis, released from IgE-sensitized basophils when exposed to antigens. Convincing evidence shows that AGEPC is synthesized by inflammatory cells, and its mechanism of action has been extensively studied with particular interest focusing on platelet stimulation, the key event initiating the inflammatory cascade. However, widely different results have been reported so that the mode of action of AGEPC in activating platelets is still largely obscure. The objective of this investigation was to elucidate whether AGEPC stimulates human platelets independently from arachidonate metabolism, as previously suggested, and to define the role of nonsteroidal antiinflammatory drugs in inhibiting AGEPC-mediated platelet activation. Irreversible platelet aggregation in vitro occurred at low AGEPC concentrations, was dose dependent, and was accompanied by thromboxane A2 formation. Aspirin inhibited irreversible aggregation induced by low AGEPC concentrations. A thromboxane inhibitor, UK-37, 248-01, failed to affect AGEPC aggregation, suggesting a crucial role for cyclic endoperoxides in AGEPC's mechanism of action. A thromboxane/endoperoxide receptor antagonist 13-azaprostanoic acid prevented irreversible platelet aggregation induced by low AGEPC concentrations. The inhibiting effect of aspirin on AGEPC aggregation could be overcome by increasing the concentration of the agonist by a factor of 10, unless a lipoxygenase inhibitor, nordihydroguaiaretic acid, or 5,8,11,14-eicosatetraynoic acid was previously added to platelet-rich plasmas. The phospholipase inhibitor, mepacrine, completely suppressed human platelet aggregation induced by AGEPC. These results indicate that AGEPC induces irreversible aggregation in human platelets by two distinct pathways, both dependent upon arachidonic acid metabolism: a cyclooxygenase-dependent one at low AGEPC concentrations and a cyclooxygenase-independent one, possibly mediated through the formation of lipoxygenase products, at high AGEPC concentrations.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1983

45Ca fluxes in isolated toad bladder epithelial cells: effects of agents which alter water or sodium transport.

Vasopressin enhances osmotic water flow and sodium transport across the toad urinary bladder by mechanisms involving cyclic AMP and calcium. It is believed that changes in intracellular calcium concentration or in its binding to membranes may in part mediate the effects of vasopressin. In addition, several agents which alter the response of the toad bladder to vasopressin may also act by altering cellular calcium metabolism. The effects of vasopressin and several agents which modify its effects in the toad bladder were studied on 45Ca fluxes in isolated epithelial cells from the toad bladder. Compartmental analysis of 45Ca exchange revealed three components. Vasopressin reduced the amount of calcium in the most rapidly exchanging pool from 1.67 +/- 0.20 to 0.86 +/- 0.12 nmol/mg of protein (P less than .025) and the most slowly exchanging pool from 2.72 +/- 0.26 to 1.90 +/- 0.34 nmol/mg of protein (P less than .001), while not affecting the intermediate pool. Theophylline, which mimics the natriferic and hydroosmotic effects of vasopressin, also mimicked the effects on 45Ca exchange by vasopressin. Exogenous cyclic AMP and the prostaglandin endoperoxide analog U46619, which mimic the hydroosmotic effect of vasopressin, also reduced the amount of calcium in the most slowly exchanging pool. Prostaglandin E1, which inhibits the hydroosmotic effect of vasopressin at the concentrations used increased the size of the most slowly exchanging pool. These studies suggest that prostaglandins and other agents which alter the effect of vasopressin in the isolated toad bladder may elicit their effects in part by influencing the calcium concentration at some critical site.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

The contractile mechanism of beraprost sodium, a stable prostacyclin analog, in the isolated canine femoral vein.

The vascular contractile mechanism of prostacyclin (PGI2) was investigated using beraprost sodium (BPS), a stable PGI2 analog. Ring strips without endothelium isolated from canine femoral veins and arteries were used. BPS induced a dose-dependent contraction without precontraction and after precontraction with norepinephrine (NE) or 60 mM K+ in the veins. In contrast, BPS induced a dose-dependent relaxation after precontraction with U46619, a thromboxane A2 (TXA2) analog, or prostaglandin F2 alpha (PGF2 alpha) in the veins. In the arteries, BPS induced contraction at higher concentrations after precontraction with NE. However, BPS relaxed arteries dose-dependently after precontraction with PGF2 alpha. By pretreatment with 13-azaprostanoic acid (13-APA), a TXA2/endoperoxide receptor antagonist, the dose-response curve of BPS in the veins was shifted to the right. Schild plot analysis resulted in a linear regression with a slope of 0.86 +/- 0.13, which was not significantly different from unity, and the pA2 value for 13-APA against BPS was 7.10 +/- 0.06. By pretreatment with BPS, the dose-response curve of U46619 in the veins was shifted to the right. Kaumann plot analysis resulted in a linear regression with a slope of 0.89 +/- 0.09, which was not significantly different from unity, and the pA2 value for BPS against U46619 was 5.68 +/- 0.04. These findings indicate that BPS is a partial agonist for the TXA2/endoperoxide receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

A new strategy for cyclopentenone synthesis.

[reaction--see text] A new strategy for the synthesis of 2,3-disubstituted cyclopentenones emerges from two key reactions-the ruthenium-catalyzed three-component coupling of an equivalent of HBr, an alkyne, and a vinyl ketone and the Ni-Cr Barbier type reaction. As a result, these important structures are readily accessed from an alkyne and a vinyl ketone (which derive directly from carboxylic acids). Syntheses of tetrahydrodicranenone B and rosaprostol illustrate the new strategy.

Anti-Infective Agents↗
PubMed1990

Effects of acetylsalicylic acid and paracetamol alone and in combination on prostanoid synthesis in man.

1. The present study was designed to investigate the effects of acetylsalicylic acid and paracetamol given separately and in combination on total body and renal PGE2 synthesis in healthy volunteers. 2. In a randomized four-way cross-over study eleven female volunteers received for two consecutive days 3 g day-1 acetylsalicylic acid or 3 g day-1 paracetamol or a combination of 1.5 g day-1 acetylsalicylic acid and 1.5 g day-1 paracetamol, or 1.5 g day-1 acetylsalicylic acid separated by washout phases of at least 5 days. Urinary excretion of the major urinary metabolite of PGE2 (PGE-MUM), PGE2 and creatinine clearance were measured before and on day 2 of each treatment period. Compliance was tested by measuring metabolites of the two drugs in urine. 3. Paracetamol did not reduce urinary excretion of PGE2 whereas both dosages of acetylsalicylic acid caused a significant reduction. 4. The combination of both drugs did not reduce PGE2 excretion more than acetylsalicylic acid alone. 5. All four drug schedules reduced urinary excretion of PGE-MUM significantly.

Acetaminophen↗
PubMed1994

Characterization of dilator prostanoid receptors in the fetal rabbit ductus arteriosus.

The purpose of this study was to determine which receptors mediate the dilator effects of prostaglandins (PGs) on the ductus arteriosus of the fetal rabbit. Isolated rings of the vessel from fetal New Zealand White rabbits were precontracted with indomethacin (1 microM) and potassium (25 mM) in 100 to 110 mmHg oxygen, and the dilator effects of a range of synthetic prostanoids were quantified by cumulative relaxant concentration-effect curves. The potencies of agonists were quantified with reference to PGE2 by the equieffective molar ratio (EMR): EC50 test agonist/EC50 PGE2. The effects on these responses of available antagonists were also studied. None of a range of synthetic prostanoids with selective agonism of EP1, EP2 or EP3 receptors was as potent as PGE2. The rank order of potency was as follows: PGE2 (EC50 = 0.36 nM [95% confidence intervals [CI] = 0.32-0.41, n = 44], EMR = unity) >> misoprostol (EMR 145, 95% CI 73-217) > [1R-[1 alpha (Z),2 beta (R*),3 alpha]]-4-(benzoyl-amino)phenyl 7-[3 hydroxy-2(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl]-4-heptenoate, single enantiomer (GR 63799K) (EMR 685, 95% CI 427-944) >> ((+/-)-trans-2-[4[(1-hydroxphenyl) phenyl]-5-oxocylopentaneheptanoic acid (AH13205) (EMR > 100,000) > or = sulprostone (EMR > 10,000) > or = 0. The EP1 antagonists, 6-isopropoxy-9-oxoxanthine-2-carboxylic acid (AH6809) (10 microM) and 8-clorodi-benz[b,f][1,4]oxazepine-10 (11H)-carboxylic acid, 2-acetylhydrazide (SC19220) (30 microM), had no significant effect on the sensitivity of the ductus to PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗