Erratum to “Discovery and SAR development of 2-(phenylamino) imidazolines as prostacyclin receptor antagonists”

Clark, Robin D.; Jahangir, Alam; Severance, Daniel L.; Salazar, Rick; Chang, Thomas K. H.; Chang, David J.; Jett, Mary‐Frances; Smith, S.; Bley, Keith

doi:10.1016/j.bmcl.2004.02.030

Cited by 23 publications

(31 citation statements)

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“…prior to iloprost application (23). As shown in Figure 1, D and E, blocking of the IP receptor completely reversed the iloprostinduced suppression of eosinophilic airway inflammation.…”

Section: Effect Of Iloprost Inhalation During Ova Challenge On Airwaymentioning

confidence: 63%

Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function

Idzko¹,

Hammad²,

Nimwegen³

et al. 2007

J. Clin. Invest.

114

115

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Inhalation of iloprost, a stable prostacyclin (PGI 2 ) analog, is a well-accepted and safe treatment for pulmonary arterial hypertension. Although iloprost mainly acts as a vasodilator by binding to the I prostanoid (IP) receptor, recent evidence suggests that signaling via this receptor also has antiinflammatory effects through unclear mechanisms. Here we show in a murine model of asthma that iloprost inhalation suppressed the cardinal features of asthma when given during the priming or challenge phase. As a mechanism of action, iloprost interfered with the function of lung myeloid DCs, critical antigen-presenting cells of the airways. Iloprost treatment inhibited the maturation and migration of lung DCs to the mediastinal LNs, thereby abolishing the induction of an allergen-specific Th2 response in these nodes. The effect of iloprost was DC autonomous, as iloprost-treated DCs no longer induced Th2 differentiation from naive T cells or boosted effector cytokine production in primed Th2 cells. These data should pave the way for a clinical effectiveness study using inhaled iloprost for the treatment of asthma.

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“…prior to iloprost application (23). As shown in Figure 1, D and E, blocking of the IP receptor completely reversed the iloprostinduced suppression of eosinophilic airway inflammation.…”

Section: Effect Of Iloprost Inhalation During Ova Challenge On Airwaymentioning

confidence: 63%

Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function

Idzko¹,

Hammad²,

Nimwegen³

et al. 2007

J. Clin. Invest.

114

115

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“…Additionally, a decrease in G i expression in SHR platelets can enhance the responsiveness to forskolin and to agonists activating receptors positively coupled to adenylate cyclase (3,10). The inhibitory effects of prostacyclin and beraprost were reversed by the IP receptor antagonist CAY-10441, confirming the involvement of IP receptors (8,27). In platelets, the IP receptor is predominantly coupled to the adenylate cyclase pathway (54) and cAMP-elevating agents are potent inhibitors of platelet activation (58).…”

Section: Discussionmentioning

confidence: 99%

Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats

Gomez

Schwendemann²,

Roger³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Gomez E, Schwendemann C, Roger S, Simonet S, Paysant J, Courchay C, Verbeuren TJ, Félétou M. Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats. Am J Physiol Heart Circ Physiol 295: H2198 -H2211, 2008. First published September 26, 2008 doi:10.1152/ajpheart.00507.2008.-In spontaneously hypertensive rat (SHR) aorta, prostacyclin is an endotheliumderived contracting factor contributing to the endothelial dysfunction. This study was designed to determine whether the impairment of the prostacyclin response is influenced by aging and whether such a dysfunction is observed in platelets. Isometric tension was measured in aortic rings, and aggregation was studied in platelet-rich plasma taken from 3-, 6-, and 15-mo-old Wistar-Kyoto rats (WKY) and SHR. In aorta from 3-and 6-mo-old WKY, prostacyclin and beraprost [prostacyclin receptor (IP) agonists] produced relaxations that were enhanced by Triplion (thromboxane-prostanoid receptor antagonist). In 15-mo-old WKY, the relaxations to beraprost were maintained, but not those to prostacyclin. In SHR aorta, prostacyclin or beraprost produced no or minor relaxations, which, in younger SHR, were enhanced by Triplion. In both strains, the relaxations were inhibited by CAY-10441 (IP receptor antagonist). The relaxations to forskolin and isoproterenol were reduced with aging. When compared with those of WKY, the relaxations to isoproterenol were reduced in 3-but not in 6-or 15-mo-old SHR, whereas those to forskolin were consistently diminished at any given age. Whatever the age, prostacyclin and beraprost produced CAY-10441-sensitive inhibitions of ADPinduced platelet aggregation. Both agonists were more potent in SHR than in WKY. Therefore, in platelets from WKY and SHR, the IP receptor-dependent antiaggregant response is functional and maintained during aging. In aorta from WKY those responses are reduced by aging and, in SHR, are already compromised at 3 mo. This dysfunction of the IP receptor is only partially explained by a general dysfunction of the adenylate cyclase pathway. smooth muscle; prostacyclin receptor; endothelium-derived contracting factors; endothelial dysfunction; spontaneously hypertensive rats; Wistar-Kyoto rats ENDOTHELIAL DYSFUNCTION IS a generic term that encompasses many different disorders (15). In the genetic model of spontaneously hypertensive rats (SHR), the endothelial dysfunction is attributed to the release of endothelium-derived contracting factors (EDCF) that counterbalances the effect of nitric oxide (NO) with no or minor alteration in the production of the latter (35). In response to acetylcholine, the endothelium-dependent contraction involves the production of reactive oxygen species, the activation of cyclooxygenase-1, the diffusion of EDCF, and the subsequent stimulation of thromboxane-prostanoid (TP) receptors on vascular smooth muscle. Since inhibitors of thromboxane synthase do not affect the endothelium-dependent contraction to acetylcholine, thromboxane A 2 is not the EDCF released by the muscarinic agonist ...

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“…In order to determine whether 8-iso-PGF 2α activates the receptors for PGI 2 (IPR), PGD 2 (DPR) or PGE 2 (EP 2 R), antagonists specific to each of these receptors were employed, i.e., CAY10441 (IPR specific) [25]; BW A868C (DPR specific) [26]; and AH 6809 (EP 2 R specific) [27]. Consistent with their reported specificity, the results demonstrated that each of these antagonists only inhibited cAMP production (Fig.…”

Section: -Iso-pgf2 α Raises Camp Independent Of the Receptors For Pgmentioning

confidence: 99%

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

Khasawneh

Huang

Mir

et al. 2008

Biochemical Pharmacology

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Since isoprostanes are thought to participate in the pathogenesis of thrombosis, presumably through their interaction with thromboxane receptors (TPRs), we examined the ability of 8-iso-PGF 2α to bind/signal through TPRs. Using TPR expressing HEK cells, it was found that 8-iso-PGF 2α mobilized calcium and bound TPRs with a dissociation constant (K d ) of 57 nM. Interestingly, site-directed-mutagenesis revealed that 8-iso-PGF 2α has a unique coordination profile with TPRs. Thus, while Phe 184 and Asp 193 are shared by both 8-iso-PGF 2α and classical TPR ligands, Phe 196 was found to be required only for 8-iso-PGF 2α binding. Functional studies also revealed interesting results. Namely, that 8-iso-PGF 2α signals in human platelets through both a stimulatory (TPR-dependent) and an inhibitory (cAMP-dependent) pathway. Consistent with the existence of two signaling pathways, platelets were also found to possess two separate binding sites for 8-iso-PGF 2α . While the stimulatory site is represented by TPRs, the second cAMP inhibitory site is presently unidentified, but does not involve receptors for PGI 2 , PGD 2 or PGE 2 . In summary, these studies provide the first documentation that: (1) 8-iso-PGF 2α coordinates with Phe 184 , Asp 193 and Phe 196 on platelet TPRs; (2) Phe 196 serves as a unique TPR binding site for 8-iso-PGF 2α ; (3) 8-iso-PGF 2α signals through both stimulatory and inhibitory pathways in platelets; (4) 8-iso-PGF 2α inhibits human platelet activation through a cAMP-dependent mechanism; (5) 8-iso-PGF 2α interacts with platelets at two separate binding sites. Collectively, these results provide evidence for a novel isoprostane function in platelets which is mediated through a cAMP-coupled receptor.

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Erratum to “Discovery and SAR development of 2-(phenylamino) imidazolines as prostacyclin receptor antagonists”

Cited by 23 publications

References 0 publications

Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function

Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function

Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats

Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets

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