Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Guan, You-Fei; Zhang, Yahua; Wu, Jing; Qi, Zhonghua; Yang, Guangrui; Dou, Dou; Gao, Yuansheng; Chen, Lihong; Zhang, Xiaoyan; Davis, Linda S.; Wei, Ming-Feng; Fan, Xueliang; Carmosino, Monica; Hao, Chuan‐Ming; Imig, John D.; Breyer, Richard M.; Breyer, Matthew D.

doi:10.1172/jci29838

Cited by 100 publications

(124 citation statements)

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“…Male mice (6-12 weeks old), wild-type, EP3 receptor knockout (Y. Zhang, C. E. Swan, K. I. Boyd, A. Bian, A. Shintani, D. Lee, D. W. Threadgill, R. C. Harris, R. Zent, and R. M. Breyer, manuscript in preparation), or EP1 receptor knockouts (Guan et al, 2007), all on C57BL/6 background, were euthanized using carbon dioxide followed by cervical dislocation. Adrenal glands were quickly harvested and placed in ice-cold magnesium-free Locke's solution containing 153 mM NaCl, 6 mM KCl, 2 mM NaH 2 PO 4 ⅐ 7H 2 O, 1 mM NaH 2 PO 4 ⅐ H 2 O, 10 mM glucose, and mM 10 HEPES.…”

Section: Methodsmentioning

confidence: 99%

“…One strategy to reduce these unwanted side effects is to identify specific cellular functions of EP receptors and develop EP receptor subtype-selective drugs. For example, characterization of EP receptor signaling in smooth muscle suggests that EP1 receptors could be targeted for antihypertensive treatment, and an EP3 receptor antagonist (2E)-3-[l- [(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl]-N- [(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041) is under investigation for treatment of atherothrombosis (Guan et al, 2007;Heptinstall et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Jewell¹,

Breyer²,

Currie³

2011

Mol Pharmacol

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Prostaglandin (PG) E 2 controls numerous physiological functions through a family of cognate G protein-coupled receptors (EP1-EP4). Targeting specific EP receptors might be therapeutically useful and reduce side effects associated with nonsteroidal antiinflammatory drugs and selective cyclooxygenase-2 inhibitors that block prostanoid synthesis. Systemic immune challenge and inflammatory cytokines have been shown to increase expression of the synthetic enzymes for PGE 2 in the adrenal gland. Catecholamines and other hormones, released from adrenal chromaffin cells in response to Ca 2ϩ influx through voltage-gated Ca 2ϩ channels, play central roles in homeostatic function and the coordinated stress response. However, long-term elevation of circulating catecholamines contributes to the pathogenesis of hypertension and heart failure. Here, we investigated the EP receptor(s) and cellular mechanisms by which PGE 2 might modulate chromaffin cell function. PGE 2 did not alter resting intracellular [Ca 2ϩ ] or the peak amplitude of nicotinic acetylcholine receptor currents, but it did inhibit Ca V 2 voltage-gated Ca 2ϩ channel currents (I Ca ). This inhibition was voltage-dependent and mediated by pertussis toxin-sensitive G proteins, consistent with a direct G␤␥ subunit-mediated mechanism common to other G i/o -coupled receptors. mRNA for all four EP receptors was detected, but using selective pharmacological tools and EP receptor knockout mice, we demonstrated that EP3 receptors mediate the inhibition of I Ca . Finally, changes in membrane capacitance showed that Ca 2ϩ -dependent exocytosis was reduced in parallel with I Ca . To our knowledge, this is the first study of EP receptor signaling in mouse chromaffin cells and identifies a molecular mechanism for paracrine regulation of neuroendocrine function by PGE 2 .

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Jewell¹,

Breyer²,

Currie³

2011

Mol Pharmacol

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“…Recent findings have shown that administration of the EP1 receptor antagonist SC51322, or selective genetic disruption of the EP1 receptor, reduces blood pressure and is, thus, a potential target for the treatment of hypertension. 23 The diverse nature of PGE 2 -mediated effects highlights the need for selective pharmacological targeting of specific inflammatory PG signaling pathways. Structure-function studies of enzymes and receptors relevant to PG signaling pathways, coupled with the availability of high-throughput screening methods, should drive the development of novel compounds that selectively target specific PGs with diminished adverse effects, relative to more broadly acting COX inhibitors (Figure 1).…”

Section: The Prostaglandin Biosynthesis Quandarymentioning

confidence: 99%

Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways

et al. 2008

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“…In the periphery, the EP4 receptor mediates vasodilation (Hristovska et al, 2007), whereas EP3, and perhaps EP1 and EP2, receptors mediate vasoconstriction (Kennedy et al, 1999;Guan et al, 2007;Chen et al, 2012). It is worth noting that the central EP3 receptor also mediates BP elevation (Ariumi et al, 2002;Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E₂ in Conscious Rats

Rezq

Abdel‐Rahman

2016

J Pharmacol Exp Ther

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Whereas few studies have dealt with the central sympathoexcitatory action of the inflammatory prostanoid prostaglandin E 2 (PGE 2 ), there is no information on the expression and cardiovascular function of different PGE 2 (EP) receptors in one of the major cardiovascular-regulating nuclei, the rostral ventrolateral medulla (RVLM). The current study aimed at filling this knowledge gap as well as elucidating the implicated molecular mechanisms. To achieve these goals, we showed the expression of EP2, EP3, and EP4 receptors in the RVLM and investigated their cardiovascular roles in conscious rats, ex vivo as well as in cultured PC12 cells. Intra-RVLM PGE 2 significantly increased blood pressure and sympathetic dominance (spectral analysis). Studies with selective EP receptor subtype agonists and antagonists showed that these PGE 2 -evoked responses were only replicated by intra-RVLM activation of the EP3 receptor with its agonist sulprostone. The RVLM of PGE 2 -treated rats exhibited increases in c-Fos expression and extracellular signal-regulated kinase 1/2 and neuronal nitric oxide synthase phosphorylation along with oxidative stress, and PGE 2 increased L-glutamate release in PC12 cells (surrogates of RVLM neurons). Abrogation of the PGE 2 -evoked pressor and biochemical responses only occurred following EP3 receptor blockade (N-[(5-Bromo-2-methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide, L-798106). These findings suggest the dependence of RVLM PGE 2 -mediated sympathoexcitation/ pressor response on local EP3 receptor signaling in conscious rats, and highlight central EP3 receptor blockade as a potential therapeutic modality for hypertension management.

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Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Cited by 100 publications

References 61 publications

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E₂ in Conscious Rats

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Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Cited by 100 publications

References 61 publications

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

Contact Info

Product

Resources

About

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E₂ in Conscious Rats