Endothelial dysfunction, which leads to ischemic events under atherosclerotic conditions, can be attenuated by antagonizing the thromboxane-prostanoid receptor (TP) that mediates the vasoconstrictor effect of prostanoids including prostacyclin (PGI2). This study aimed to determine whether antagonizing the E prostanoid receptor-3 (EP3; which can also be activated by PGI2) adds to the above effect of TP deficiency (TP–/–) under atherosclerotic conditions and if so, the underlying mechanism(s). Atherosclerosis was induced in ApoE–/– mice and those with ApoE–/– and TP–/–. Here, we show that in phenylephrine pre-contracted abdominal aortic rings with atherosclerotic lesions of ApoE–/–/TP–/– mice, although an increase of force (which was larger than that of non-atherosclerotic controls) evoked by the endothelial muscarinic agonist acetylcholine to blunt the concurrently activated relaxation in ApoE–/– counterparts was largely removed, the relaxation evoked by the agonist was still smaller than that of non-atherosclerotic TP–/– mice. EP3 antagonism not only increased the above relaxation, but also reversed the contractile response evoked by acetylcholine in NO synthase-inhibited atherosclerotic ApoE–/–/TP–/– rings into a relaxation sensitive to I prostanoid receptor antagonism. In ApoE–/– atherosclerotic vessels the expression of endothelial NO synthase was decreased, yet the production of PGI2 (which evokes contraction via both TP and EP3) evoked by acetylcholine was unaltered compared to non-atherosclerotic conditions. These results demonstrate that EP3 blockade adds to the effect of TP–/– in uncovering the dilator action of natively produced PGI2 to alleviate endothelial dysfunction in atherosclerotic conditions.

Although recognized to have an in vivo vasodepressor effect blunted by the vasoconstrictor effect of E-prostanoid receptor-3 (EP3), prostaglandin E 2 (PGE 2 ) evokes contractions of many vascular beds that are sensitive to antagonizing the thromboxane prostanoid receptor (TP). This study aimed to determine the direct effect of PGE 2 on renal arteries and/or the whole renal vasculature and how each of these two receptors is involved in the responses. Experiments were performed on isolated vessels and perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP −/− ), EP3 (EP3 −/− ), or both TP and EP3 (TP −/− /EP3 −/− ). Here we show that PGE 2 (0.001-30 μM) evoked not only contraction of main renal arteries, but also a decrease of flow in perfused kidneys. EP3 -/diminished the response to 0.001-0.3 μM PGE 2 , while TP −/− reduced that to the prostanoid of higher concentrations. In TP −/− /EP3 −/− vessels and perfused kidneys, PGE 2 did not evoke contraction but instead resulted in vasodilator responses. These results demonstrate that PGE 2 functions as an overall direct vasoconstrictor of the mouse renal vasculature with an effect reflecting the vasoconstrictor activities outweighing that of dilation. Also, our results suggest that EP3 dominates the vasoconstrictor effect of PGE 2 of low concentrations (≤0.001-0.3 μM), but its effect is further added by that of TP, which has a higher efficacy, although activated by higher concentrations (from 0.01 μM) of the same prostanoid PGE 2 . K E Y W O R D S EP3, gene deficiency, PGE 2 , renal vasoconstriction, TP | 2569 LIU et aL. How to cite this article: Liu B, Wu X, Zeng R, et al. Prostaglandin E 2 sequentially activates E-prostanoid receptor-3 and thromboxane prostanoid receptor to evoke contraction and increase in resistance of the mouse renal vasculature.

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Background. Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon, and clinical outcome of UC is still unsatisfied. Pingkui enema, a traditional Chinese medicine prescription, has been safely applied for the treatment of diarrhea and dysentery in clinic for many years. However, its mechanism is still elusive. The present study is designed to investigate the effect of Pingkui enema on trinitrobenzene sulfonic acid- (TNBS-) induced ulcerative colitis (UC) and possible mechanism in rats. Methods. UC was induced by intracolonic instillation of TNBS in male Sprague-Dawley rats, which were treated with different dosages of Pingkui enema (low, medium, and high) or sulfasalazine for ten days. Survival rate was calculated. A clinical disease activity score was evaluated. Histological colitis severity was analyzed by hematoxylin-eosin (HE) staining. Content of Bifidobacterium in intestinal tissue was analyzed by RT-PCR. Concentration of IL-8, IL-13, TNF-α, D-lactic acid (D-LA), and diamine oxidase (DAO) in serum and contents of adhesin and receptor of Bifidobacterium adhesion in rat intestinal mucus were measured by ELISA. Results. The results showed that Pingkui enema treatment with high dosage markedly improved the survival rate compared with untreated and sulfasalazine treated groups. All dosages of Pingkui enema reduced pathological score. High dosage of Pingkui enema and sulfasalazine treatments significantly reduced the serum concentration of IL-8, TNF-α, D-LA, and DAO and markedly increased the serum concentration of IL-13. In addition, high-dose Pingkui enema and sulfasalazine treatments increased gut content of Bifidobacterium, gut mucus expressions of adhesin, and adhesin receptor of Bifidobacterium. Conclusions. Pingkui enema has therapeutic effect on TNBS-induced UC, and possible mechanism may be via regulation of gut probiotics (Bifidobacterium) and inflammatory factors and protection of intestinal mucosal barrier.