Background:In experimental glomerulonephritis, inhibition of cyclooxygenase 2 (COX-2) enhances the renocortical expression of pathogenic αvintegrins.Aims:To study whether this effect is mediated by prostaglandin E2(PGE2) acting through its EP3receptor in cultured rat mesangial cells (MCs).Methods:MCs were incubated with lipopolysaccharide (LPS), celecoxib, PGE2, or the selective EP3agonist, MB28767. The expression of COX-2, EP3, and αvintegrin mRNA was measured by reverse transcriptase polymerase chain reaction.Results:LPS upregulated COX-2 expression 2.8-fold and αvintegrin expression twofold. The COX-2 inhibitor celecoxib increased αvintegrin mRNA expression twofold. Both exogenous PGE2and the specific EP3receptor agonist, MB28767, reduced constitutive αvintegrin mRNA expression to half normal values. COX-2 dependent PGE2suppressed the expression of αvintegrin mRNA mediated by the EP3receptor in MCs.Conclusions:These results suggest that COX-2 suppresses the expression of αvintegrins by an increased production of PGE2activating its EP3receptor in glomerulonephritis.

2000-05-01·Hypertension1区 · 医学

Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E ₂ Receptors

1区 · 医学

Article

作者: Breyer, Matthew D. ; Zhang, Yahua ; Schneider, André ; Breyer, Richard M. ; Brandon, Suzanne ; Guan, YouFei

Abstract —Four E-prostanoid (EP) receptors, designated EP 1 , EP 2 , EP 3 , and EP 4 , mediate the cellular effects of prostaglandin E 2 (PGE 2 ). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP 2+/+ mice) and mice with targeted disruption of the EP 2 receptor (EP 2−/− mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE 2 decreased MAP in EP 2+/+ mice but increased MAP in EP 2−/− mice. Infusion of EP 3 -selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP 2+/+ and EP 2−/− mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE 2 in EP 2+/+ mice remained intact. Although PGE 2 alone increased MAP in EP 2−/− mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE 2 to be seen in the EP 2−/− mice. An EP 4 -selective agonist (prostaglandin E 1 -OH) functioned also as a vasodepressor in both EP 2−/− and EP 2+/+ mice. High levels of EP 3 receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP 1 , EP 2 , and EP 4 mRNA. The findings suggest that combined vasodepressor effects of EP 2 and EP 4 receptors normally dominate, accounting for the depressor effects of PGE 2 . In contrast, in EP 2−/− mice, EP 4 receptor activity alone is insufficient to overcome the EP 3 vasopressor effect. These findings suggest that a balance between pressor and depressor PGE 2 receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.

1997-10-01·Brain Research4区 · 医学

Biphasic modulation in the trigeminal nociceptive neuronal responses by the intracerebroventricular prostaglandin E2 may be mediated through different EP receptors subtypes in rats

4区 · 医学

Article

作者: Takakazu Oka ; Chiharu Kubo ; Michie Abe ; Masako Hosoi ; Kae Oka ; Tetsuro Hori

To determine which prostaglandin E2 (PGE2) receptor subtypes are involved in the brain-derived PGE2-induced changes in nociception, we injected synthetic EP1, EP2 and EP3 receptor agonists (0.01 fmol to 10 nmol) into the lateral cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus caudalis to noxious pinching of facial skin. The enhancement and suppression of the nociceptive responses of the WDR neurons were observed after the LCV injection of MB28767 (an EP3 receptor agonist) at a low dose range (1-100 fmol) and 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist) at high doses (1-10 nmol), respectively. Furthermore, the suppression of nociceptive neuronal responses after the LCV injection of PGE2 (1 nmol) was completely blocked by SC19220 (an EP1 receptor antagonist, 300 nmol). On the other hand, butaprost (an EP2 receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl-omega-trinor PGE2 (1 nmol), which respectively enhanced and suppressed the nociceptive neuronal responses, did not affect the responses of the low threshold mechanoreceptive neurons to innocuous tactile stimuli. These results provide electrophysiological evidence that brain-derived PGE2 induces mechanical hyperalgesia and hypoalgesia through EP3 and EP1 receptors, respectively, in the rat.

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