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15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic acid

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Description

15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic acid, often abbreviated as **15-HETE-epoxide**, is a bioactive lipid compound that belongs to the family of **eicosanoids**, specifically **epoxyeicosatrienoic acids (EETs)**. It is a derivative of **arachidonic acid**, a fatty acid found in cell membranes.

**Structure and Formation:**

* **15-HETE-epoxide** is formed through a series of enzymatic steps. First, arachidonic acid is metabolized by **15-lipoxygenase** to form **15-hydroxyeicosatetraenoic acid (15-HETE)**.
* Subsequently, **cytochrome P450 enzymes**, particularly **CYP2C** and **CYP2J**, catalyze the epoxidation of 15-HETE, yielding **15-HETE-epoxide**.

**Biological Activity and Importance in Research:**

**15-HETE-epoxide exhibits a wide range of biological effects, making it a significant subject of research:**

* **Cardiovascular effects:** It has been shown to **relax blood vessels**, potentially impacting blood pressure and circulation. This effect is attributed to its interaction with **K+ channels** in vascular smooth muscle cells.
* **Inflammation:** 15-HETE-epoxide has been implicated in **anti-inflammatory responses**. Its mechanism of action involves inhibiting the production of pro-inflammatory mediators like **tumor necrosis factor alpha (TNF-α)**.
* **Neuroprotection:** Studies suggest a role for 15-HETE-epoxide in **protecting neurons from damage**, possibly by reducing oxidative stress and promoting cell survival.
* **Cancer:** 15-HETE-epoxide has shown **anti-cancer activity** in some studies. It can inhibit the growth of certain cancer cells and induce apoptosis (programmed cell death).
* **Metabolic regulation:** 15-HETE-epoxide has been linked to **glucose metabolism** and **insulin sensitivity**. Its potential involvement in these processes warrants further investigation.

**Research Applications:**

* **Drug discovery:** 15-HETE-epoxide is a promising target for the development of novel drugs for treating cardiovascular diseases, inflammatory conditions, neurodegenerative disorders, and cancer.
* **Biomarkers:** Measuring levels of 15-HETE-epoxide in biological samples (blood, urine) could provide valuable information about the status of various diseases and physiological processes.
* **Understanding Eicosanoid Signaling:** Research on 15-HETE-epoxide contributes to a better understanding of the intricate signaling pathways mediated by eicosanoids, a critical aspect of cellular communication and regulation.

**Challenges and Future Directions:**

* **Specificity:** Developing methods to selectively target specific receptors and pathways activated by 15-HETE-epoxide is crucial for developing safe and effective drugs.
* **In vivo studies:** More in vivo studies are needed to validate the therapeutic potential of 15-HETE-epoxide and to investigate its long-term effects on different organ systems.
* **Metabolic Stability:** 15-HETE-epoxide is prone to enzymatic degradation, which can limit its bioavailability. Developing strategies to enhance its stability in the body is important for therapeutic applications.

**Overall, 15-HETE-epoxide is a fascinating and promising compound with potential therapeutic applications in various fields. Continued research is crucial to unravel its intricate biological roles and translate its potential into clinical benefits.**

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid: A stable prostaglandin endoperoxide analog which serves as a thromboxane mimetic. Its actions include mimicking the hydro-osmotic effect of VASOPRESSIN and activation of TYPE C PHOSPHOLIPASES. (From J Pharmacol Exp Ther 1983;224(1): 108-117; Biochem J 1984;222(1):103-110) [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID SourceID
PubMed CID5354027
MeSH IDM0029372

Synonyms (6)

Synonym
15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic acid
15-hydroxy-11alpha,9alpha-(epoxymethano)prosta-5,13-dienoic acid
5-heptenoic acid, 7-(6-(3-hydroxy-1-ocentyl)-2-oxabicyclo(2.2.1)hept-5-yl)-
7-(6-(3-hydroxy-1-ocentyl)-2-oxabicyclo(2.2.1)hept-5-yl)-5-heptenoate
76898-47-0
(e)-7-[6-[(e)-3-hydroxyoct-1-enyl]-2-oxabicyclo[2.2.1]heptan-5-yl]hept-5-enoic acid

Research Excerpts

Toxicity

ExcerptReferenceRelevance
"Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA."( Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects.
Aida, T; Fujita, T; Ichikawa, Y; Minamisawa, S; Yokota, T; Yokoyama, U, 2012
)
0.38

Pharmacokinetics

ExcerptReferenceRelevance
" 4 Across the dose range, vapiprost was rapidly cleared from plasma, with an elimination half-life of 69-84 min and a plasma clearance of 514-721 ml min-1."( The pharmacodynamics and pharmacokinetics of a novel thromboxane receptor blocking drug vapiprost (GR32191) after single intravenous doses in healthy subjects.
Charter, MK; Chilton, JE; Keery, RJ; Lumley, P; Scully, NL; Thomas, M, 1991
)
0.28
"A selective thromboxane A2 (TXA2) receptor blocking agent, vapiprost, was orally administered to healthy male Japanese volunteers to investigate the pharmacokinetic and pharmacodynamic properties."( Pharmacokinetic and pharmacodynamic profiles of vapiprost, a selective, long-lasting thromboxane receptor antagonist, after single and multiple oral administration to healthy volunteers.
Hirano, K; Mizuno, A; Nagashima, S; Nakashima, M; Uematsu, T, 1991
)
0.28
"The pharmacokinetics and pharmacodynamic effect on platelet activation of a single 800 mg oral dose of BM 13."( Single dose pharmacokinetics and effects on platelet function of the thromboxane receptor blocker BM 13.177.
Endele, R; Kaufmann, B; Neugebauer, G; Patscheke, H; Staiger, C; Stegmeier, K; Strein, K, 1986
)
0.27
" Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination."( Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.
Granneman, GR; Hussein, Z; Locke, CS; Orchard, MA; Ringham, GL; Samara, E, 1994
)
0.29
" In the single-dose study (200, 300, 400 mg), the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) increased non-linearly with dose, while the mean elimination half-life (V0) was essentially unchanged (3."( Pharmacokinetic and pharmacodynamic properties of FK070 (KDI-792), a novel thromboxane receptor antagonist/thromboxane synthetase inhibitor, after single and multiple oral administrations to healthy volunteers.
Kosuge, K; Nakano, M; Nakashima, M; Terakawa, M; Uematsu, T; Umemura, K, 1996
)
0.29
"Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown."( Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.
Breitenbach, CS; Ghofrani, HA; Grimminger, F; Hildebrand, M; Kurz, J; Schermuly, RT; Schulz, A; Seeger, W; Weissmann, N, 2006
)
0.33

Compound-Compound Interactions

ExcerptReferenceRelevance
"Differential effects on human platelet function of thromboxane A2 (TXA2) synthetase inhibition singly and of TXA2 synthetase inhibition combined with TXA2/prostaglandin endoperoxide receptor antagonism were revealed, using ridogrel as a probe."( Effect of thromboxane A2 synthetase inhibition, singly and combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on inositol phospholipid turnover and on 5-HT release by washed human platelets.
de Chaffoy de Courcelles, D; De Clerck, F, 1990
)
0.28
" The pulmonary vasodilation obtained with NO alone could be prolonged from 12 to 42 min when inhaled NO was combined with IV dipyridamole, accounting for a time-weighted reduction in NO exposure by 72%."( Intermittent nitric oxide combined with intravenous dipyridamole in a piglet model of acute pulmonary hypertension.
De Somer, F; De Wolf, D; Foubert, L; Mortier, E; Reyntjens, K; Van Belleghem, Y; Van Nooten, G, 2003
)
0.32
" Intermittent NO inhalation combined with IV dipyridamole decreases pulmonary artery pressure for a prolonged period of time and reduces exposure to NO."( Intermittent nitric oxide combined with intravenous dipyridamole in a piglet model of acute pulmonary hypertension.
De Somer, F; De Wolf, D; Foubert, L; Mortier, E; Reyntjens, K; Van Belleghem, Y; Van Nooten, G, 2003
)
0.32
"To investigate the effects of propofol combined with indomethacin on the contractile function of isolated human pulmonary arteries."( [Effects of propofol combined with indomethacin on contraction of isolated human pulmonary arteries].
Cui, JX; Deng, CY; Hao, N; Kuang, SJ; Ma, J; Zhang, GY, 2017
)
0.46
" The intrapulmonary arteries were dissected and cut into rings under microscope for treatment with propofol or propofol combined with indomethacin."( [Effects of propofol combined with indomethacin on contraction of isolated human pulmonary arteries].
Cui, JX; Deng, CY; Hao, N; Kuang, SJ; Ma, J; Zhang, GY, 2017
)
0.46

Bioavailability

ExcerptReferenceRelevance
" The good bioavailability and the long duration of action of some of these compounds was demonstrated using ex vivo measurement of the TxRA activity upon oral administration to guinea pigs."( Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 4. 8-[[(4-Chlorophenyl)sulfonyl]amino]-4-(3-(3-pyridinyl) propyl)octanoic acid and analogs.
Bhagwat, SS; Boswell, C; Cohen, DS; Contardo, N; Dotson, R; Furness, P; Gude, C; Lee, W; Mathis, J; Zoganas, H, 1992
)
0.28
" This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound."( Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylalkyl)octanoic acid.
Bhagwat, SS; Cohen, DS; Dotson, R; Furness, P; Gude, C; Lee, W; Mathis, J, 1993
)
0.29
" During steady flow, the bioavailability of NO is sufficient to cause vasodilation."( Effect of steady versus oscillating flow on porcine coronary arterioles: involvement of NO and superoxide anion.
Sorop, O; Spaan, JA; Sweeney, TE; VanBavel, E, 2003
)
0.32
"Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O(2)(*-)) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO)."( Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells.
Angelini, GD; Jeremy, JY; Muzaffar, S; Shukla, N; Srivastava, A, 2005
)
0.33
" (i) The bioavailability (i."( Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.
Breitenbach, CS; Ghofrani, HA; Grimminger, F; Hildebrand, M; Kurz, J; Schermuly, RT; Schulz, A; Seeger, W; Weissmann, N, 2006
)
0.33
" EDHF was likely the sole mediator responsible for the direct effects of LPC on U-46619-vasoconstriction, whereas the augmented vasoconstrictor responses following LPC washout may in part be related to an increase in ET-1, and a striking reduction in the bioavailability of NO."( The ischemic metabolite lysophosphatidylcholine increases rat coronary arterial tone by endothelium-dependent mechanisms.
Bai, N; Laher, I; MacLeod, KM; Rodrigues, B; So, J; Zhang, R, 2009
)
0.35
" Likely arachidonic acid reducing NO bioavailability through all these mechanisms could potentiate its platelet aggregating power."( The arachidonic acid effect on platelet nitric oxide level.
Leoncini, G; Segantin, A; Signorello, MG, 2009
)
0.35
"Endothelial dysfunction has been linked to a decrease in nitric oxide (NO) bioavailability and attenuated endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation."( Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats.
Carneiro, FS; Carneiro, ZN; Dorrance, A; Giachini, FR; Lima, VV; Tostes, RC; Webb, RC, 2009
)
0.35
"Statins can have beneficial cholesterol-independent effects on vascular contractility, which may involve increases in the bioavailability of NO (nitric oxide) as a result of phosphorylation of eNOS (endothelial NO synthase)."( Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries.
Al-Abri, M; Austin, C; Cobb, C; Rossoni, LV; Wareing, M; Wenceslau, CF, 2011
)
0.37
" Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity."( Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways.
Castranova, V; Chen, BT; Frazer, DG; Knuckles, TL; Leonard, HD; Nurkiewicz, TR; Yi, J, 2012
)
0.38
"Vascular tone is controlled by the L-arginine/nitric oxide (NO) pathway, and NO bioavailability is strongly affected by hyperglycaemia-induced oxidative stress."( Insulin reverses D-glucose-increased nitric oxide and reactive oxygen species generation in human umbilical vein endothelial cells.
Aguayo, C; Avila, P; Cabrera, L; Gallardo, V; González, M; Guzmán-Gutiérrez, E; Leiva, A; Palma, C; Pardo, F; Peña, E; Rojas, S; Sáez, T; Salsoso, R; Sanhueza, C; Sobrevia, L; Villalobos, R, 2015
)
0.42
"Endothelial dysfunction is associated with a reduced bioavailability of nitric oxide (NO)."( Long-term nitric oxide synthase inhibition prevents 17β-estradiol-induced suppression of cyclooxygenase-dependent contractions and enhancement of endothelium-dependent hyperpolarization-like relaxation in mesenteric arteries of ovariectomized rats.
Leung, SWS; Shi, Y, 2020
)
0.56

Dosage Studied

ExcerptRelevanceReference
" Dose-response curves for U-46619 and U-44069 were shifted to the right in a parallel manner, and daltroban had no significant effect on responses to norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin-(ET) 1, ET-2, or platelet-activating factor (PAF)."( Daltroban blocks thromboxane responses in the pulmonary vascular bed of the cat.
Babycos, CR; Hood, JS; Ibrahim, IN; Kadowitz, PJ; McMahon, TJ; Nossaman, BD, 1992
)
0.28
" The present study was undertaken to determine whether nocturnal dosage with S-1452, a thromboxane A2 receptor antagonist, would blunt the morning rise in platelet aggregability."( Effect of treatment at night with S-1452, a thromboxane A2 receptor antagonist, on the morning rise in platelet aggregation.
Ebihara, A; Fujimura, A; Kumagai, K; Ohashi, K, 1992
)
0.28
" The muscarinic antagonists pirenzepine, (+-)-5,11-dihydro-11-[[[2-[2-((dipropylamino)methyl)-1-piperidinyl] ethyl]amino]-carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AF-DX 384), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro- 6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one (AQ-RA 741), p-fluorohexahydro-sila-difenidol (p-F-HHSiD), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and (R)- and (S)-hexahydro-difenidol [(R)-HHD, (S)-HHD] shifted the muscarine, methacholine or carbachol dose-response curve to the right in a competitive manner."( Characterization of muscarinic receptors mediating vasodilation in guinea-pig ileum submucosal arterioles by the use of computer-assisted videomicroscopy.
Bungardt, E; Feifel, R; Lambrecht, G; Moser, U; Mutschler, E; Surprenant, A; Tacke, R; Vockert, E, 1992
)
0.28
"1 mg/kg iv, responses to U-46619 and U-44069 were reduced significantly, and the dose-response curves for these TxA2 mimics were shifted to the right in a parallel manner at a time when responses to PGF2 alpha and PGD2 were not altered."( Characterization of thromboxane receptor blocking effects of SQ 29548 in the feline pulmonary vascular bed.
Hood, JS; Hyman, AL; Kadowitz, PJ; McMahon, TJ; Nossaman, BD, 1992
)
0.28
" In contrast, L-NNA caused a leftward shift in the dose-response relationship to the thromboxane mimetic U-46619, indicating that the endogenous release of EDRF modulates the pulmonary vascular response to this vasoconstrictor."( N omega-nitro-L-arginine and pulmonary vascular pressure-flow relationship in conscious dogs.
Desai, PM; Murray, PA; Nishiwaki, K; Nyhan, DP; Peterson, WP; Pribble, CG; Rock, P, 1992
)
0.28
"Arachidonic acid (AA)- or thromboxane A2/prostaglandin H2 (TXA2/PGH2) analog (STA2 and U-46619)-induced aggregations yielded a bell-shaped dose-response curve."( Elevation of platelet cyclic AMP level by thromboxane A2/prostaglandin H2 receptor agonists.
Ishikawa, Y; Ogawa, A, 1991
)
0.28
" Dose-response curves were obtained to bolus injections of 5-hydroxytryptamine (5-HT) in Krebs'-perfused hindquarters of male Wistar rats."( Thromboxane A2 receptor stimulation similarly potentiates pressor responses to 5-hydroxytryptamine in perfused hindquarters of non-diabetic and alloxan diabetic rats.
Hodgson, WC; King, RG; Sikorski, BW, 1991
)
0.28
" Following the administration of SQ 29,548, pressor responses to both U44069 and U46619 were reduced significantly, and the dose-response curves for both TXA2 mimics were shifted to the right in a parallel fashion."( Influence of SQ 29,548 on vasoconstrictor responses in the hindquarters vascular bed of the cat.
Bellan, JA; Kadowitz, PJ; McMahon, TJ; McNamara, DB; Minkes, RK, 1991
)
0.28
" SQ 30741 had no significant effect on mean vascular pressures in the cat, and the dose-response curve for U-46619 was shifted to the right in a parallel manner with a similar apparent maximal response."( Influence of SQ 30741 on thromboxane receptor-mediated responses in the feline pulmonary vascular bed.
Feng, CJ; Hood, JS; Ibrahim, IN; Kadowitz, PJ; McMahon, TJ; Nossaman, BD, 1991
)
0.28
" The dose-response curves for inhibition of ex vivo platelet aggregation and a fall in mean arterial blood pressure were compared."( Primate vascular responses to octimibate, a non-prostanoid agonist at the prostacyclin receptor.
Brown, AM; Bund, S; Cooper, DG; Egan, JW; Hallam, TJ; Heagerty, AM; Hickey, DM; Kaumann, AJ; Keen, M; Merritt, JE, 1991
)
0.28
" Multiple dosing with GR32191, 17."( Preliminary assessment of a novel thromboxane A2 receptor-blocking drug, GR32191, in healthy subjects.
Lumley, P; Thomas, M, 1990
)
0.28
"1-fold (n = 3) shift to the right in the U-46,619 dose-response for renal vasoconstriction."( Activity of the short-acting thromboxane receptor antagonist, SQ 30,741, in thrombolytic and vasospastic models in monkeys.
Hartl, KS; Heran, CL; Ogletree, ML; Schumacher, WA, 1990
)
0.28
" The PAF receptor antagonism with BN 50730 was overcome when 10-fold larger doses of PAF were administered and the dose-response curves for changes in lung resistance and dynamic compliance were shifted to the right in a parallel manner."( Influence of SK&F 95587 and BN 50730 on bronchoconstrictor responses in the cat.
Beckerman, RC; Bellan, JA; Braquet, P; Dyson, MC; Kadowitz, PJ; McNamara, DB; Minkes, RK; Wegmann, MJ, 1990
)
0.28
" Topical application of exogenous PGF2 alpha and U46619 resulted in dose-dependent cerebral vasoconstriction, and the dose-response curve for each agonist was shifted to the right by the increasing concentrations of SQ29548 (10(-6)-10(-8) M)."( Effect of thromboxane A2/endoperoxide antagonist SQ29548 on the contractile response to acetylcholine in newborn piglet cerebral arteries.
Busija, DW; Wagerle, LC, 1990
)
0.28
" At 6 h post DE, there were no differences between the dose-response curves obtained from aortic rings with or without endothelium."( Effect of endothelium removal on stimulatory and inhibitory modulation of rat aortic prostacyclin synthesis.
Dandona, P; Jeremy, JY, 1989
)
0.28
" Consistent with this hypothesis were (i) a 60-70% decrease in SQ 26,655-stimulated platelet GTPase activity, (ii) a shift to the right of the dose-response curve for U46619-stimulated release of calcium [EC50, 275 +/- 51 nM (control)] vs."( Regulation of thromboxane receptor activation in human platelets.
FitzGerald, GA; Murray, R, 1989
)
0.28
" Removal of the endothelium or the presence of Hb caused significant shifts of the dose-response curves to the left and further increases in maxima."( Effects of endothelial cell removal on constrictor and dilator responses of aortae of pregnant rats.
Boura, AL; Jansakul, C; King, RG, 1989
)
0.28
" When dosed orally to anaesthetized guinea-pigs, ICI 180080 (5-50 mg kg-1) caused dose-related inhibition of U-46619-evoked bronchoconstriction."( Pharmacological actions of ICI 180080, a novel thromboxane receptor antagonist.
Jessup, CL; Jessup, R; Wayne, M, 1986
)
0.27
" In addition, analysis of dose-response curves to U46619 (0."( Thromboxane A2 and prostaglandin endoperoxide receptors in platelets and vascular smooth muscle.
Halushka, PV; Knapp, DR; Mais, DE; Saussy, DL, 1985
)
0.27
"In normocapnic and deeply hypocapnic guinea-pig heart-lung-preparations (HLPs), dose-response relationships were estimated for the bronchoconstrictor and pulmonary hypertensive responses to histamine (H), 5 hydroxytryptamine (5HT), arachidonic acid (AA) and U-46619, a prostaglandin endoperoxide analogue acting on thromboxane (TXA2) receptors."( Arachidonic acid and pulmonary function in heart-lung-preparation of guinea-pig: modulation by PCO2.
Argiolas, L; Bedetti, C; Carpi, A; Del Basso, P, 1987
)
0.27
" The effect of PTA2 on U46619 and CTA2 was dose-dependent over the dosage range of PTA2 tested (1."( U46619 and carbocyclic thromboxane A2-induced increases in tracheal mucous gel layer thickness.
Foxwell, MH; Smith, WL; Yanni, JM, 1988
)
0.27
" Dose-response curves to each agonist were generated in random order, and tantalum bronchograms and simultaneous measurements of pulmonary resistance (RL) and dynamic pulmonary compliance (Cdyn) were obtained at the plateau of the response of each dose of agonist after intravenous (iv) infusion."( Distribution of airway contractile responses within the major diameter bronchi during exogenous bronchoconstriction.
Leff, AR; Mack, M; Munoz, NM; Shioya, T; Solway, J, 1987
)
0.27
" Oral dosing with U46619 or AH23848 produced a dose-related inhibition of ethanol-induced gastric mucosal damage in the conscious rat, and these effects were partially blocked by indomethacin treatment."( The effects of the stable thromboxane A2-mimetic, U46619, on gastric mucosal damage and gastric non-parietal secretion in the rat.
Bunce, KT; Clayton, NM, 1987
)
0.27
" 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."( Antagonism of prostanoid-induced vascular contraction by 13-azaprostanoic acid (13-APA).
Horn, PT; Kohli, JD; LeBreton, GC; Venton, DL,
)
0.13
" Contractility was examined in a randomized dose-response manner to both norepinephrine and the prostaglandin endoperoxide analog U-46619."( Vascular reactivity in endotoxin shock: effect of lidocaine or indomethacin pretreatment.
Casey, L; Fletcher, JR; Pomerantz, K; Ramwell, PW, 1982
)
0.26
" Variation in tension with time (2 h) and the dose-response to thromboxane A2 analogue (U46619) and phenylephrine (PE) were measured in controls and treated rings."( Effect of rapamycin on rat aortic ring vasomotion.
Blaise, GA; Chen, H; Corbin, F; Daloze, PM; Parent, M, 1994
)
0.29
" The peptides produced dose-related increases in perfusion pressure, and dose-response curves to all six peptides were parallel."( Analysis of responses to angiotensin peptides in the hindquarters vascular bed of the cat.
Garrison, EA; Kadowitz, PJ; Osei, SY; Santiago, JA, 1995
)
0.29
" infused over 2 min; n = 4-8 per group) produced a bell-shaped dose-response curve for MPAP and haematocrit, and evoked maximal increases of 12."( Intrinsic activity of the non-prostanoid thromboxane A2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo.
Bertolino, F; Bessac, AM; Colpaert, FC; Delhon, A; Grelac, F; Lévy-Toledano, S; Maclouf, J; Maffre, M; Patoiseau, JF; Valentin, JP, 1995
)
0.29
" The dose-response curve was shifted to the left, and the maximum effect was increased."( Effect of estradiol 17 beta on pressor responses of rat mesenteric bed to norepinephrine, K+, and U-46619.
Delaney, M; Farhat, MY; Ramwell, PW; Rego, A; Vargas, R; Wolfe, R, 1995
)
0.29
" In addition, pulmonary vascular reactivity was assessed by examining the dose-response relationship to the thromboxane analogue U-46619 pre- and post-CPB."( Prolonged pulmonary vascular hyperreactivity in conscious dogs after cardiopulmonary bypass.
Gillinov, AM; Murray, PA; Nishiwaki, K; Nyhan, DP; Redmond, JM, 1994
)
0.29
" Increases in perfusion pressure in response to bolus injections of U46619 were used to construct dose-response curves."( Reduced thromboxane receptor affinity and vasoconstrictor responses in placentae from diabetic pregnancies.
Hollander, AM; Mento, PF; Wilkes, BM, 1994
)
0.29
" 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."( The contractile mechanism of beraprost sodium, a stable prostacyclin analog, in the isolated canine femoral vein.
Ishikawa, M; Namiki, A, 1994
)
0.29
" With KCl (100 mM) serving as the control, the dose-response curves to norepinephrine, serotonin, and thromboxane A2 mimetic were obtained, permitting assessment of force of contraction and sensitivity."( Vasoreactivity of the radial artery. Comparison with the internal mammary and gastroepiploic arteries with implications for coronary artery surgery.
Acar, C; Carpentier, A; Chardigny, C; Descombes, JJ; Fabiani, JN; Jebara, VA; Verbeuren, TJ, 1993
)
0.29
" Dose-response curves (DRC) of U 46619-induced platelet aggregation were analysed by computerized non-linear curve fitting."( Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists.
Clemens, MR; Jaschonek, K; Kirchner, M; Scheurlen, M, 1993
)
0.29
" Selective PAF, TXA2 and 5HT antagonists (WEB 2086, sulotroban and MCI-9042) clearly inhibited both the shape change and the aggregation induced by the appropriate agonist; in each case the effect of the antagonist was to move the dose-response curve to the right."( Studies on the effects of agonists and antagonists on platelet shape change and platelet aggregation in whole blood.
Heptinstall, S; Lösche, W; Sanderson, HM; Vickers, J, 1996
)
0.29
"9 h after dosing with food."( Effect of food intake on pharmacokinetics and effects of a new thromboxane A2 receptor antagonist, S-1452.
Ebihara, A; Fujimura, A; Kotegawa, T; Kumagai, Y; Ohashi, K; Shiga, T, 1996
)
0.29
"These results suggest that although the absorption of S-1452 is delayed and, consequently, its plasma concentration is decreased after dosing with food, the inhibitory effect on platelet aggregation is not significantly influenced after 50 mg of the drug."( Effect of food intake on pharmacokinetics and effects of a new thromboxane A2 receptor antagonist, S-1452.
Ebihara, A; Fujimura, A; Kotegawa, T; Kumagai, Y; Ohashi, K; Shiga, T, 1996
)
0.29
" We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions."( Effects of zaprinast and dissolved nitric oxide on the pulmonary circulation of fetal sheep.
Cassin, S; DeMarco, VG; Kadowitz, PJ; Skimming, JW, 1996
)
0.29
") administered 30 min before and 6 h after antigen challenge (double dosing regimen), did not affect the development of the early or late phase responses."( Effects of inhibitors of phosphodiesterase, on antigen-induced bronchial hyperreactivity in conscious sensitized guinea-pigs and airway leukocyte infiltration.
Broadley, KJ; Danahay, H, 1997
)
0.3
"5 kg) were infused with randomly selected doses of U46,619 and of 8-epi-PGF2 alpha to describe dose-response curves plotting pulmonary vascular resistance (PVRi) against dose."( Effects of 8-epi-prostaglandin F2 alpha and U46,619 on pulmonary hemodynamics in piglets.
Norberg, M; Thibeault, DW; Truog, WE, 1997
)
0.3
"Discrete dose-response curves were obtained for the response to 5-HT (0."( Changes in reactivity towards 5-hydroxytryptamine in the renal vasculature of the diabetic spontaneously hypertensive rat.
Boston, PC; Hodgson, WC, 1997
)
0.3
" Threshold concentrations of ET-1 increased the maximum response to 5-HT, and markedly shifted the dose-response curve to the left."( Interactions between vasoconstrictors in isolated human cerebral arteries.
Barth, HL; Hempelmann, RG; Mehdorn, HM; Pradel, RH; Ziegler, A, 1997
)
0.3
" Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation."( Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.
Grimminger, F; Mayer, K; Otterbein, J; Schütte, H; Seeger, W; Spriestersbach, R; Walmrath, D, 1997
)
0.3
"The stable thromboxane A2 mimetic, U46619, was infused in increasing dosage to obtain a stable pulmonary hypertension of approximately 30 mm Hg."( Efficacy of inhaled prostanoids in experimental pulmonary hypertension.
Habler, O; Hofstetter, C; Kleen, M; Mueller, M; Pusch, R; Welte, M; Zwissler, B, 1998
)
0.3
" Male Sprague-Dawley rats were pretreated with either subcutaneous nicotine or equivolume saline and a dose-response curve for dopaminergic pulmonary vasodilation was constructed ex vivo in isolated, salt-perfused rat lungs preconstricted with the synthetic thromboxane analogue U-46619."( Acute nicotine pretreatment augments dopaminergic pulmonary vasodilation.
Russ, RD, 1998
)
0.3
" We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine."( Inhibition of endogenous nitric oxide synthesis potentiates the effects of sodium nitroprusside but not of adenosine in experimental pulmonary hypertension.
Kavanagh, BP; Patterson, KW; Pearl, RG; Wall, MH, 1999
)
0.3
" After reducing perfusion pressure to 20 mmHg for 30 min and reperfusing at 80 mmHg, the dose-response curve to U46619 was unaffected."( The vasoconstrictor effect of 8-epi prostaglandin F2alpha in the hypoxic rat heart.
Kromer, BM; Tippins, JR, 1999
)
0.3
" Therefore, the objective of this study was to determine the potential dose-response interactions of inhaled NO, oxygen, and alkalosis therapies."( Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension.
Bekker, JM; Fineman, JR; Heidersbach, RS; Johengen, MJ, 1999
)
0.3
" Each of the inhibitors attenuated ANG II-induced reductions in MBF, and all dose-response curves were shifted to the right to an approximately threefold higher ANG II dose."( ANG II- and TxA(2)-induced mesenteric vasoconstriction in rats is mediated by separate cell signaling pathways.
Bauer, J; Cavarape, A; Dau, C; Ehmke, H; Parekh, N; Schaefer, F, 1999
)
0.3
" In contrast, the dose-response curve of the adrenergic agonist phenylephrine was significantly attenuated for the estradiol-replaced rats compared with the ovariectomized group (EC(50)=0."( Effect of estrogen replacement on vasoconstrictor responses in rat mesenteric arteries.
Davidge, ST; Zhang, Y, 1999
)
0.3
" Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner."( Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation.
Brosnihan, KB; Diz, DI; Ferrario, CM; Fukuhara, M; Li, P, 2000
)
0.31
" The addition of superoxide dismutase (SOD), 100 U/ml produced a shift to the left in the antiaggregant dose-response curve for XOR."( Inhibition of platelet aggregation with glyceryl trinitrate and xanthine oxidoreductase.
Benjamin, N; Blake, D; Millar, T; O'Byrne, S; Shirodaria, C; Stevens, C, 2000
)
0.31
"The U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-response manner."( [Effect of losartan on human platelet activation by thromboxane A2].
Casado, S; Castilla, C; Farré, J; Gómez, J; Guerra, JI; Jiménez, AM; López-Farré, A; Marcos, P; Montón, M; Núñez, A; Rico, L; Rodríguez-Feo, JA; Sánchez De Miguel, L, 2000
)
0.31
" The intralipid vehicle for propofol had no effect on the acetylcholine dose-response relation."( Propofol selectively attenuates endothelium-dependent pulmonary vasodilation in chronically instrumented dogs.
Kim, SO; Kondo, U; Murray, PA, 2000
)
0.31
" In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial effects of PAF (1 - 32 ng) were carried out in the absence or presence of L-NNA (200 microM)."( Nitric oxide (NO) modulation of PAF-induced cardiopulmonary action: interaction between NO synthase and cyclo-oxygenase-2 pathways.
Calabrese, R; del Basso, P; Fabi, F; Stati, T, 2001
)
0.31
" U-46619 evoked a sharp decrease in microvessel diameter within a 10(-7)-10(-4)M gamut, with the dose-response profiles at 5- and 10-min timepoints remaining essentially parallel over the tested range of concentrations."( Vascular activities of prostaglandins and selective prostanoid receptor agonists in human retinal microvessels.
Nieves, AL; Spada, CS; Woodward, DF, 2002
)
0.31
" Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME)."( Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats.
Ajayi, AA; Cory, J; Hayes, BE; Hercule, H; Oyekan, AO, 2003
)
0.32
" Rightward shift of the dose-response curves due to coinfusion of inhibitors served to assess contribution of different pathways: trimethoxybenzoate (TMB-8) against Ca2+ mobilization, nifedipine against Ca2+ influx, staurosporine and Ro-318220 against PKC, and Y-27632 and HA-1077 against ROK."( Variations in cell signaling pathways for different vasoconstrictor agonists in renal circulation of the rat.
Bauer, J; Parekh, N, 2003
)
0.32
" They shifted dose-response curves of Ang II, norepinephrine, and AVP to sevenfold and higher values."( Variations in cell signaling pathways for different vasoconstrictor agonists in renal circulation of the rat.
Bauer, J; Parekh, N, 2003
)
0.32
"1 microM), or the cyclooxygenase enzyme (COX) inhibitor diclofenac (10 microM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL."( Interactions among three classes of mediators explain antigen-induced bronchoconstriction in the isolated perfused and ventilated guinea pig lung.
Dahlén, SE; Låstbom, L; Ryrfeldt, A; Sundström, E, 2003
)
0.32
" The dose-response curve for ACh in the OVX group was quite similar to that obtained with the Sham group."( Estrogen-induced augmentation of endothelium-dependent nitric oxide-mediated vasodilation in isolated rat cerebral small arteries.
Ikomi, F; Momoi, H; Ohhashi, T, 2003
)
0.32
" Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10 min before each U-46619 injection."( Effects of U-46619 on pulmonary hemodynamics before and after administration of BM-573, a novel thromboxane A2 inhibitor.
Benoit, P; D'Orio, V; Dogné, JM; Gérard, P; Ghuysen, A; Kolh, P; Lambermont, B; Limet, R; Masereel, B; Morimont, P; Tchana-Sato, V, 2003
)
0.32
" Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA(2) interaction with ET-antagonists BQ610 and BQ788."( Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes: studies in gonadectomized and sham-operated Zucker diabetic rats.
Ajayi, AA; Ogungbade, GO; Okorodudu, AO, 2004
)
0.32
"The objectives of the study were to (1) characterize the dose-response relationship to the TXA2 analog, U46619 (0."( Estrogen restores postischemic sensitivity to the thromboxane mimetic U46619 in rat pial artery.
Hurn, PD; Littleton-Kearney, MT; Qin, X, 2005
)
0.33
" Dose-response curves were produced with the thromboxane-mimetics U46619 and U44069 (10(-10)-2 x 10(-6)M), arginine vasopressin (10(-10)-5 x 10(-8)M) and endothelin-1 (10(-11)-3 x 10(-7)M) in the presence or absence of 50 micromol l(-1) glibenclamide."( Glibenclamide inhibits agonist-induced vasoconstriction of placental chorionic plate arteries.
Baker, PN; Fyfe, GK; Greenwood, SL; Taggart, MJ; Wareing, M,
)
0.13
"Pre-incubation with 50 micromol l(-1) glibenclamide significantly right-shifted dose-response curves to all vasoconstrictive agonists tested (repeated measures ANOVA)."( Glibenclamide inhibits agonist-induced vasoconstriction of placental chorionic plate arteries.
Baker, PN; Fyfe, GK; Greenwood, SL; Taggart, MJ; Wareing, M,
)
0.13
" Twelve anesthetized pigs were randomly assigned in two groups: in Ago group (n=6), the animals received six consecutive injections of U-46619 at 30 min interval, while in Anta group (n=6) they received an increasing dosage regimen of BM-573 10 min before each U-46619 injection."( Effects of BM-573, a thromboxane A2 modulator on systemic hemodynamics perturbations induced by U-46619 in the pig.
D'Orio, V; Dogné, JM; Ghuysen, A; Hanson, J; Kolh, P; Lambermont, B; Limet, R; Magis, D; Morimont, P; Tchana-Sato, V, 2005
)
0.33
" This desensitization was not dependent on upregulation of cAMP-specific phosphodiesterases or changes in adenylate cyclase activity, as suggested by unaltered dose-response curves to agents directly affecting these enzymes."( Iloprost-induced desensitization of the prostacyclin receptor in isolated rabbit lungs.
Breitenbach, SC; Ghofrani, HA; Grimminger, F; Kirchrath, JM; Nilius, SM; Pullamsetti, SS; Rose, F; Schermuly, RT; Schrör, K; Seeger, W; Weissmann, N, 2007
)
0.34
" Dose-response curve was bell shaped with a maximum effect at 10 nmol per site."( Thromboxane A2 induces itch-associated responses through TP receptors in the skin in mice.
Andoh, T; Kuraishi, Y; Narumiya, S; Nishikawa, Y; Nojima, H; Yamaguchi-Miyamoto, T, 2007
)
0.34
" Dose-response curves were constructed for NE with and without the addition of the alpha-adrenergic antagonist prazosin, EPI (after 20%-30% preconstruction with the thromboxane analog U46619) with and without the addition of the beta-adrenergic antagonist propranolol, and NE in the presence of 10(-8) M EPI."( The effect of maternal catecholamines on the caliber of gravid uterine microvessels.
Segal, S; Wang, SY, 2008
)
0.35
" The dose-response to vasoconstrictors and vasodilators was assessed in small resistance coronary arteries."( Effect of fetal anaemia on myocardial ischaemia-reperfusion injury and coronary vasoreactivity in adult sheep.
Davis, LE; Giraud, GD; He, GW; Hohimer, AR; Underwood, MJ; Van Winkle, DM; Yang, Q, 2008
)
0.35
"There was no difference in the tension dose-response to U46619 between the normoxic fetal and hypoxic fetal left anterior descending, although [Ca(2+)](i) was lower in the hypoxic fetal than normoxic fetal at the highest doses."( The effect of long-term hypoxia on tension and intracellular calcium responses following stimulation of the thromboxane A(2) receptor in the left anterior descending coronary artery of fetal sheep.
Gilbert, RD; Maruko, K; Stiffel, VM, 2009
)
0.35
" Injection of small (100 to 200 microm) or large (355 to 425 microm) polystyrene beads and incremental dosage (0."( Comparison of 3 methods to induce acute pulmonary hypertension in pigs.
Baumert, JH; Hein, M; Roehl, AB; Rossaint, R; Schnoor, J; Steendijk, P, 2009
)
0.35
" The dose-response curve was shifted to the left in both cases, suggesting increased MK reactivity."( Acetylsalicylic acid enhances purinergic receptor-mediated outward currents in rat megakaryocytes.
Beckerman, J; Myers, A; Vicini, S; Young, JP, 2010
)
0.36
" Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu."( Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.
Brass, LF; Chatterjee, MS; Diamond, SL; Purvis, JE, 2010
)
0.36
" Collagen and U46619 caused in vivo thrombus formation with the former, but not latter, sensitive to oral dosing with aspirin."( Thrombosis is reduced by inhibition of COX-1, but unaffected by inhibition of COX-2, in an acute model of platelet activation in the mouse.
Armstrong, PC; Emerson, M; Kirkby, NS; Mitchell, JA; Warner, TD; Zain, ZN, 2011
)
0.37
" Dose-response curves to both prostanoids were competitively shifted to the right by all antagonists, but to different extents."( Thromboxane and isoprostane share the same prostanoid receptors to increase human placental tone.
Hausermann, L; St-Louis, J, 2011
)
0.37
"Placental and myometrial arteries were mounted on a wire myograph, exposed to the constrictor U46619 (10(-10) to 10(-5) m), returned to baseline tension, and then incubated with IGF-I (0-500 ng/ml) for various time points before performing a second dose-response curve to U46619."( Differential effect of insulin like growth factor-I on constriction of human uterine and placental arteries.
Charnock, JC; Corcoran, JJ; Martin, J; Taggart, MJ; Westwood, M, 2012
)
0.38
" COX selectivity was determined from dose-response curves by calculating a ratio (COX-2/COX-1) of IC50 values."( In vitro pharmacological evaluation of multitarget agents for thromboxane prostanoid receptor antagonism and COX-2 inhibition.
Bertinaria, M; Buccellati, C; Capra, V; Carnevali, S; Cena, C; Fruttero, R; Garella, D; Hoxha, M; Rolando, B; Rovati, GE; Sala, A, 2016
)
0.43
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (2,498)

TimeframeStudies, This Drug (%)All Drugs %
pre-1990364 (14.57)18.7374
1990's1017 (40.71)18.2507
2000's735 (29.42)29.6817
2010's333 (13.33)24.3611
2020's49 (1.96)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 6.81

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be weak demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index6.81 (24.57)
Research Supply Index7.87 (2.92)
Research Growth Index4.68 (4.65)
Search Engine Demand Index0.00 (26.88)
Search Engine Supply Index0.00 (0.95)

This Compound (6.81)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials27 (1.05%)5.53%
Reviews12 (0.47%)6.00%
Case Studies11 (0.43%)4.05%
Observational1 (0.04%)0.25%
Other2,526 (98.02%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]