Dataset Information

PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors.

ABSTRACT:

Background and purpose

The guinea pig trachea (GPT) is commonly used in airway pharmacology. The aim of this study was to define the expression and function of EP receptors for PGE(2) in GPT as there has been ambiguity concerning their role.

Experimental approach

Expression of mRNA for EP receptors and key enzymes in the PGE(2) pathway were assessed by real-time PCR using species-specific primers. Functional studies of GPT were performed in tissue organ baths.

Key results

Expression of mRNA for the four EP receptors was found in airway smooth muscle. PGE(2) displayed a bell-shaped concentration-response curve, where the initial contraction was inhibited by the EP(1) receptor antagonist ONO-8130 and the subsequent relaxation by the EP(2) receptor antagonist PF-04418948. Neither EP(3) (ONO-AE5-599) nor EP(4) (ONO-AE3-208) selective receptor antagonists affected the response to PGE(2). Expression of COX-2 was greater than COX-1 in GPT, and the spontaneous tone was most effectively abolished by selective COX-2 inhibitors. Furthermore, ONO-8130 and a specific PGE(2) antibody eliminated the spontaneous tone, whereas the EP(2) antagonist PF-04418948 increased it. Antagonists of other prostanoid receptors had no effect on basal tension. The relaxant EP(2) response to PGE(2) was maintained after long-term culture, whereas the contractile EP(1) response showed homologous desensitization to PGE(2), which was prevented by COX-inhibitors.

Conclusions and implications

Endogenous PGE(2), synthesized predominantly by COX-2, maintains the spontaneous tone of GPT by a balance between contractile EP(1) receptors and relaxant EP(2) receptors. The model may be used to study interactions between EP receptors.

SUBMITTER: Safholm J

PROVIDER: S-EPMC3631371 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors.

Säfholm J J Dahlén S-E SE Delin I I Maxey K K Stark K K Cardell L-O LO Adner M M

British journal of pharmacology 20130201 4

<h4>Background and purpose</h4>The guinea pig trachea (GPT) is commonly used in airway pharmacology. The aim of this study was to define the expression and function of EP receptors for PGE(2) in GPT as there has been ambiguity concerning their role.<h4>Experimental approach</h4>Expression of mRNA for EP receptors and key enzymes in the PGE(2) pathway were assessed by real-time PCR using species-specific primers. Functional studies of GPT were performed in tissue organ baths.<h4>Key results</h4>E ...[more]

PMID: 22934927

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Project description:Prostaglandin E2 (PGE2) is involved in numerous physiological and pathological processes of the kidney via its four receptors. A previous study has suggested that a defect in the PGE2 receptor 1 (EP1) gene markedly suppressed the transforming growth factor??1 (TGF??1)?induced mesangial cell (MC) proliferation and extracellular matrix aggregation. Therefore, the present study aimed to adopt a pharmacological method of specifically suppressing or activating the EP1 receptor to further verify and demonstrate these results. The EP1 receptor antagonist SC?19220 and EP1 receptor agonist 17?phenyl?trinor?PGE2 ethyl amide (17?pt?PGE2) were selectively used to treat five?sixths nephrectomy renal fibrosis model mice and TGF??1?stimulated MCs. An Alpha screen PGE2 assay kit, flow cytometry, western blotting and immunohistochemical techniques were adopted to perform in vivo and in vitro experiments. The present results suggested that compared with the control group, the selective EP1 receptor antagonist SC?19220 improved renal function, markedly reduced the plasma blood urea nitrogen and creatinine levels (P<0.05) and alleviated glomerulosclerosis (P<0.05). By contrast, the EP1 receptor agonist 17?pt?PGE2 aggravated renal dysfunction and glomerulosclerosis (P<0.05). To verify the renal protection mechanisms mediated by suppression of the EP1 receptor, the expression levels of endoplasmic reticulum stress (ERS)?related proteins, including chaperone glucose?regulated protein 78 (GRP78), transient receptor potential channel 1 (TRPC1) and protein kinase R?like endoplasmic reticulum kinase (PERK), were further evaluated histologically. The expression of GRP78, TRPC1 and PERK in the antagonist treatment group were markedly downregulated (P<0.05), whereas those in the agonist treatment group were upregulated (P<0.05). The present in vitro experiments demonstrated that, compared with the control group, the EP1 receptor antagonist suppressed the expression of GRP78, TRPC1 and PERK (P<0.05), reduced the production of PGE2 (P<0.05) and decreased the MC apoptosis rate (P<0.05), thus alleviating TGF??1?stimulated MC injury. Consequently, consistent with previous results, selectively antagonizing the EP1 receptor improved renal function and mitigated glomerulosclerosis, and its potential mechanism might be associated with the suppression of ERS.

Dataset Information

PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors.

Similar Datasets

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