Vascular Effects of Proteinase-Activated Receptor 2 Agonist Peptide

Emilsson, Kjell; Wahlestedt, Claes; Sun, Miao Kun; Nystedt, Sverker; Owman, Christer; Sundelin, Johan

doi:10.1159/000159233

Cited by 70 publications

(71 citation statements)

References 15 publications

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“…The present results clearly show that PAR-2 activation causes vasodilation in healthy humans in vivo, and in this respect, the results are similar to those seen in experimental animals. 12,13 Interestingly, in studies of isolated human vessels, pretreatment with either interleukin-1 (IL-1) or tumor necrosis factor-␣ (TNF-␣) upregulated PAR-2 expression and, in the coronary artery, revealed endothelium-dependent vasodilatation to PAR-2-activating peptides. 14 This response was abolished by either removal of the endothelium or combined treatment with N-nitro-L-arginine (an NO synthase [NOS] inhibitor) and indomethacin.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

et al. 2003

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Background-Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation. Methods and Results-For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human blood vessels in a dose-dependent manner, and the effects were reduced by inhibition of both nitric oxide and prostanoid synthesis Conclusions-These findings demonstrate that serine protease activity can cause human vasodilation and provide a possible explanation of why serine protease activation in critical illness is associated with vascular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

et al. 2003

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“…The mechanisms of PAR-2-elicited inflammation consist of multiple cascades, including increase of vascular permeability, cytokine production, and expression of adhesion molecules that further lead to leukocyte accumulation (19). Additionally, PAR-2-stilumated secretion of prostanoids (33) and NO (34) may enhance the inflammatory responses, while activation of PAR-2 in nerve endings induces the release of calcitonin gene-related peptide (CGRP) and substance P (35). Therefore, the future development of PAR-2 antagonists can be therapeutically beneficial for treatment of a number of inflammatory diseases such as allergic dermatitis, rheumatoid arthritis, asthma, inflammatory bowel disease, and neurogenic pain.…”

Section: Par-2 As a Therapeutic Targetmentioning

confidence: 99%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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Abstract. PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the Gprotein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca

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“…PAR-2 may also contribute to regulation of vascular tone, since PAR-2 mRNA is present in highly vascularized tissues 5 and application of trypsin or the PAR-2 agonist peptide produces endothelium-dependent relaxation of peripheral arteries in vitro. [6][7][8][9] Furthermore, in anesthetized rats hypotension is produced when the agonist peptide corresponding to the tethered ligand sequence in the mouse and the rat (SLIGRL) is injected intravenously, 8,9 possibly indicating that PAR-2-mediated vasodilatation also occurs in vivo.…”

Section: See Editorial Comment Page 1444mentioning

confidence: 99%

“…Previous indirect studies have indicated that PAR-2 activation may produce vasodilatation in vivo. The hypotensive effect of intravenous injection of SLIGRL was reported to be accompanied by baroreflex-mediated tachycardia and sympathetic nerve activation, 8,9 suggesting that the decrease in arterial pressure was associated with a decrease in total peripheral resistance rather than in cardiac output. The present findings, in which topical application of PAR-2 activators produced increases in basilar artery diameter in the absence of any change in systemic arterial blood pressure, confirm directly that PAR-2-mediated vasodilatation occurs in vivo in the cerebral circulation.…”

Section: Functional Importance Of Par-2mentioning

confidence: 99%

Activation of Protease-Activated Receptor-2 (PAR-2) Elicits Nitric Oxide–Dependent Dilatation of the Basilar Artery In Vivo

Sobey

Cocks

1998

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Background and Purpose-Protease-activated receptors (PARs) are a family of G-protein-coupled receptors activated by a tethered ligand amino acid sequence within the amino terminal that is revealed by site-specific proteolysis. In the vascular endothelium, activation of PAR-2 by treatment with trypsin or by using the amino acid ligand sequence (SLIGRL) produces endothelium-dependent relaxation of isolated noncerebral vascular segments. In this study, we first tested whether PAR-2 activation produces cerebral vasodilatation in vivo and then examined whether PAR-2-mediated vasodilatation is dependent on the production of nitric oxide. Methods-Concentration-dependent vasodilator effects of the PAR-2 agonist peptide SLIGRL and trypsin were examined on the basilar artery using a cranial window in anesthetized rats. In addition, the vasodilator effects of SLIGRL, acetylcholine (ACh), and sodium nitroprusside (SNP) were examined in the absence and presence of mol/L) and trypsin (0.01 to 10 U/mL) produced concentration-dependent vasodilator responses. In time-control experiments, SLIGRL (3ϫ10 -6 and 10 -5 mol/L), ACh (10 -6 and 10 -5 mol/L), and SNP (10 -8 and 10 -7 mol/L) elicited reproducible dilatation of the basilar artery. In another group of rats, L-NNA (10 -4 mol/L) markedly inhibited dilator responses to both SLIGRL (13Ϯ3% versus 1Ϯ1% and 39Ϯ7% versus 11Ϯ2%; both PϽ0.05) and ACh (8Ϯ1% versus 0Ϯ0% and 13Ϯ2% versus 3Ϯ1%; both PϽ0.05). By contrast, responses to SNP were significantly augmented after treatment with L-NNA (PϽ0.05 versus control), indicating that inhibitory effects of L-NNA were specific for responses mediated by endogenous nitric oxide. Furthermore, in another group ODQ (10 Ϫ5 mol/L) inhibited responses to SLIGRL to a degree similar to that seen with L-NNA, consistent with a mechanism of PAR-2-mediated vasodilatation that involves activation of guanylate cyclase by nitric oxide. Conclusions-To the best of our knowledge, this study is the first to examine whether PAR-2-mediated vasodilatation is functional in cerebral arteries and is also the first to directly assess the effects of PAR-2 activation on vascular tone in vivo. The results suggest that activation of PAR-2 is an effective and powerful vasodilator mechanism in cerebral arteries in vivo. Cerebral vasodilator responses to PAR-2 activation are mediated by nitric oxide and are likely to be endothelium dependent.

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Vascular Effects of Proteinase-Activated Receptor 2 Agonist Peptide

Cited by 70 publications

References 15 publications

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

Activation of Protease-Activated Receptor-2 (PAR-2) Elicits Nitric Oxide–Dependent Dilatation of the Basilar Artery In Vivo

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