Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists

Swayne, G. T. G.; Maguire, J.P.; Dolan, John S.; Raval, P.; Dane, G.; Greener, M.; Owen, David A.

doi:10.1016/0014-2999(88)90726-1

Cited by 55 publications

(9 citation statements)

References 14 publications

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“…Indeed, the spasmogenic activity of 8-iso-PGE 2 on HASM is insensitive to AH 6809 but blocked by the TP-receptor antagonist ICI 192,605 (Janssen et al, 2000). In the present study, SQ 29,548 at a concentration that is known to abolish TPreceptor-mediated signaling (Swayne et al, 1988), did not antagonize the inhibitory effect of 8-iso-PGE 1 or 8-iso-PGE 2 on GM-CSF (or G-CSF) release. Thus, in human airways, E-ring 8-isoprostanes are agonists at multiple prostanoid receptors where they can influence independently both tone and the synthetic capacity of the smooth muscle.…”

Section: Gm-csf Releasecontrasting

confidence: 59%

“…Pretreatment (30 min) of HASM cells with SQ 29,548 (1 M) or BW A868C (1 M), at concentrations that are ϳ500 and 2000 times greater than their affinity at TPand DP 1 -receptors, respectively (Swayne et al, 1988;Giles et al, 1989), failed to antagonize the effect of E-ring 8-isoprostanes [at 100 nM (ϳEC 40 ) and 10 M (ϳEC 95 )] on CSF secretion ( Fig. 5; Table 1).…”

Section: Resultsmentioning

confidence: 98%

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E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Clarke

Belvisi²,

Hardaker³

et al. 2004

Mol Pharmacol

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8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E-and F␣-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1␤ (IL-1␤). The elaboration of GM-CSF and G-CSF by IL-1␤ was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E 1 and 8-iso-PGE 2 , but not by 8-iso-PGF 1␣ , 8-iso-PGF 2␣ , and 8-iso-PGF 3␣ . AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP 1 -/ EP 2 -/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE 1 and 8-iso-PGE 2 on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP 2 -subtype. In contrast, the facilitation by 8-iso-PGE 1 and 8-iso-PGE 2 of G-CSF release was unaffected by AH 6809 and theHowever, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE 1 and 8-iso-PGE 2 concentration-response curves. The opposing effect of E-ring 8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP-and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE 1 and 8-iso-PGE 2 act solely via EP 2 -receptors to inhibit GM-CSF release, whereas both EP 2 -and EP 4 -receptor subtypes positively regulate G-CSF output.The isoprostanes embody a vast family of novel prostaglandin-like lipids that are produced by nonenzymatic peroxidation of arachidonic acid (AA) in response to free radicals and reactive oxygen species (Janssen, 2001;Morrow and Roberts, 2002). Although free AA is required for the formation of prostaglandins by cyclooxygenases, the isoprostanes can be generated nonenzymatically from esterified AA in membrane phospholipids before being released by a phospholipase(s) (Liu et al., 1999). Another dissimilarity is that isoprostanes feature side chains that are almost exclusively orientated cis relative to the cyclopentane ring and are therefore distinct from the prostaglandins, which always have side chains in the trans configuration (Morrow et al., 1990). NevArticle, publication date, and citation information can be found at

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Section: Gm-csf Releasecontrasting

confidence: 59%

Section: Resultsmentioning

confidence: 98%

E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Clarke

Belvisi²,

Hardaker³

et al. 2004

Mol Pharmacol

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“…Although there was significant correlation of pA2 values for rabbit platelets versus human or rat platelets, absolute values, with the exception of BM 13177, were lower on rabbit platelets. It is of interest that Swayne et al (1988) have reported a good correlation between the potencies of nine TP-receptor antagonists on human and rabbit platelets and have used this result to postulate homogeneity of TP-receptors. However, although a highly significant correlation (P < 0.01 using a multiple linear correlation matrix) was obtained, actual IC50 values for inhibition of U-46619-induced aggregation were always much higher (13-600 fold!)…”

Section: Compoundsmentioning

confidence: 98%

Heterogeneity of thromboxane A₂ (TP‐) receptors: evidence from antagonist but not agonist potency measurements

Tymkewycz

Jones

Wilson

et al. 1991

British J Pharmacology

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1 Thromboxane A2 (TP-) receptors in human, rat and rabbit platelets and in smooth muscle of guineapig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure. 2 On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11-azo PGH2 > 9,11-endoxy-lOa-homo PGH2 > U-46619 (standard) > PGH2 = 16-p-fluorophenoxy-co-tetranor PGF2. > 16,16-dimethyl PGF2,. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP-receptor. 3 Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20-methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration-response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20-methano PTA2 could be treated as a pure antagonist. 4 With U-46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20-methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0-1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets. 5 None of the antagonists was highly potent on the rabbit aorta (pA2 values < 7.5 by Schild analysis). Affinities on the guinea-pig trachea and the rat aorta were higher and in the same range as those obtained for human and rat platelets. However the correlations of pA2 values between any pair of smooth muscle preparations and between any pair of platelet/smooth muscle preparations were either weak or not significant (P > 0.05). 6 The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP-receptor subtypes and further suggests that the agonist recognition sites of the TP-receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP-receptors. However, classification into TP,-, TP2-receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.

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“…Pretreatment (30 min) of HASM cells with SQ 29,548 (1 M) or BW A868C (1 M), at concentrations that are ϳ500 and 2,000 times greater than their affinity at TP and DP receptors, respectively (28,62), failed to antagonize the stimulatory effect on G-CSF secretion of any of the prostanoids studied (Table 3). Fig.…”

Section: Effect Of Fluprostenol On Il-1␤-induced G-csf Releasementioning

confidence: 99%

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

Clarke¹,

Belvisi²,

Smith³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor. Am J Physiol Lung Cell Mol Physiol 288: L238 -L250, 2005; doi:10.1152/ ajplung.00313.2004.-The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1␤ of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling pathway elucidated. PCR of HASM cDNA identified products corresponding to EP 2, EP3, and EP4 receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1␤ promoted the elaboration of G-CSF, which was augmented by PGE2. Cicaprost (IP receptor agonist) was approximately equiactive with PGE2, whereas PGD2, PGF2␣, and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP1 receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE2, the EP receptor agonists 16,16-dimethyl PGE2 (nonselective), misoprostol (EP2/EP3 selective), 17-phenyl--trinor PGE2 (EP1 selective), ONO-AE1-259, and butaprost (both EP2 selective) were full agonists at enhancing G-CSF release. AH 6809 (10 M) and L-161,982 (2 M), which can be used in HASMC as selective EP2 and EP4 receptor antagonists, respectively, failed to displace to the right the PGE2 concentrationresponse curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE2-induced G-CSF release. Augmentation of G-CSF release by PGE 2 was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE2 facilitates G-CSF secretion from HASMC through a PKAdependent mechanism by acting through EP2 and EP4 prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.cAMP-dependent protein kinase; human airway smooth muscle; granulocyte colony-stimulating factor; prostanoid receptors; airway inflammation

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Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists

Cited by 55 publications

References 14 publications

E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Heterogeneity of thromboxane A₂ (TP‐) receptors: evidence from antagonist but not agonist potency measurements

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

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Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists

Cited by 55 publications

References 14 publications

E-Ring 8-Isoprostanes Are Agonists at EP2- and EP4-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

E-Ring 8-Isoprostanes Are Agonists at EP2- and EP4-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Heterogeneity of thromboxane A2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor

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E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

E-Ring 8-Isoprostanes Are Agonists at EP₂- and EP₄-Prostanoid Receptors on Human Airway Smooth Muscle Cells and Regulate the Release of Colony-Stimulating Factors by Activating cAMP-Dependent Protein Kinase

Heterogeneity of thromboxane A₂ (TP‐) receptors: evidence from antagonist but not agonist potency measurements