Protease-Activated Receptor-2 Involvement in Hypotension in Normal and Endotoxemic Rats In Vivo

Cicala, Carla; Pinto, Aldo; Bucci, Mariarosaria; Sorrentino, Raffaella; Walker, Brian; Harriot, Patrick; Cruchley, A. T.; Kapas, S.; Howells, Gareth L.; Cirino, Giuseppe

doi:10.1161/01.cir.99.19.2590

Cited by 100 publications

(114 citation statements)

References 20 publications

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“…Responses may also vary according to whether trypsin or an activating peptide is used as a pharmacological probe. 20 The present study clearly shows that in humans, there is a major role for NO in PAR-2-mediated vasodilation, at least in the forearm arterial bed.…”

Section: Discussionsupporting

confidence: 64%

“…Indeed, in a rat model, pretreatment with lipopolysaccharide substantially enhanced the sensitivity to the hypotensive response elicited by systemic administration of PAR-2-activating peptide. 20 Septic patients have a significant elevation in both circulating immunoreactive trypsin and endogenous trypsin inhibitors, 33 and immunoreactive trypsin levels have also been shown to correlate with risk of complications such as adult respiratory distress syndrome. 34 Circulating levels of trypsin are also elevated in the systemic inflammatory response observed in human acute pancreatitis, and both the overall severity of the illness 35 and the development of associated acute lung injury correlate with trypsin activity in a rat model of the disease.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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“…The present data suggest that mast cell-derived tryptase may be an important and early activator of endothelial cells in response to tissue trauma. In addition to sensing tryptase, PAR2 can be activated by the tissue factor/factor VIIa complex and by factor Xa (45). The ability of PAR2 to sense activation of the coagulation cascade provides another potential link between tissue trauma and cellular responses.…”

Section: Discussionmentioning

confidence: 99%

Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice

Lindner

Kahn

Coughlin

et al. 2000

The Journal of Immunology

252

209

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Endothelial surface expression of P-selectin and subsequent leukocyte rolling in venules can be induced by mast cell-derived histamine and binding of thrombin to protease-activated receptor-1 (PAR1). We hypothesized that activation of endothelial PAR2 by mast cell tryptase or other proteases also contributes to inflammatory responses. Leukocyte rolling flux and rolling velocity were assessed by intravital microscopy of the cremaster muscles of wild-type mice following perivenular micropipette injections of a control (LSIGRL) or PAR2-activating (SLIGRL) oligopeptide. Injection of SLIGRL increased mean rolling leukocyte flux fraction from 34 ± 11 to 71 ± 24% (p < 0.05) and decreased mean rolling velocity from 63 ± 29 to 32 ± 2 μm/s (p < 0.05). No significant changes occurred with control peptide injection. To further evaluate the role of PAR2 in inflammatory responses, PAR2-deficient mice were generated by gene targeting and homologous recombination. Perivenular injections of SLIGRL resulted in only a small increase in rolling leukocyte flux fraction (from 21 ± 8 to 30 ± 2%) and no change in rolling velocity. Leukocyte rolling after surgical trauma was assessed in 9 PAR2-deficient and 12 wild-type mice. Early (0–15 min) after surgical trauma, the mean leukocyte rolling flux fraction was lower (10 ± 3 vs 30 ± 6%, p < 0.05) and mean rolling velocity was higher (67 ± 46 vs 52 ± 36 μm/s, p < 0.01) in PAR2-deficient compared with control mice. The defect in leukocyte rolling in PAR2-deficient mice did not persist past 30 min following surgical trauma. These results indicate that activation of PAR2 produces microvascular inflammation by rapid induction of P-selectin-mediated leukocyte rolling. In the absence of PAR2, the onset of inflammation is delayed.

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“…In the endothelium-denuded preparations, carbachol had no effect on [Ca 2+ ] i , but a higher concentration of trypsin induced a small but apparent increase in [Ca 2+ ] i without muscle contraction. Trypsin activates PAR2 [16], which was expressed in both endothelial cells and smooth muscle cells of rat blood vessels [3]. These finding suggest that trypsin increases [Ca 2+ ] i not only in endothelial cells but also in smooth muscle cells in the rat aorta.…”

Section: Discussionmentioning

confidence: 73%

Effects of Trypsin on Cytosolic Calcium Levels in the Rat Aortic Endothelium

Kaneko

Komatsu

Sato

2011

The Journal of Veterinary Medical Science

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ABSTRACT. The effect of trypsin on vascular tone and the cytosolic calcium concentration ([Ca 2+ ] i ) of endothelial and smooth muscle cells were examined in the rat aorta. A calcium indicator, fura-PE3, was used to measure [Ca 2+ ] i simultaneously with vascular tone. In the endothelium-intact rat aorta, carbachol and trypsin increased [Ca 2+ ] i in a dose-dependent manner. In the endothelium-denuded rat aorta, carbachol did not change [Ca 2+ ] i , but trypsin slightly increased it. Addition of trypsin to the norepinephrine-stimulated rat aorta relaxed the muscle with an additional increase in [Ca 2+ ] i . Under calcium-free conditions, trypsin induced a transient increase in [Ca 2+ ] i . Trypsininduced endothelium-dependent relaxation was inhibited by preincubation with l-NMMA, an endothelial NO synthase inhibitor, U-73122, a phospholipase C inhibitor, cyclopiazonic acid, a sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase blocker, and lanthanum, a nonselective Ca 2+ channel blocker. However, indomethacin, a nonselective cyclooxygenase inhibitor, and SKF-96365, a store-operated Ca 2+ -channel blocker, had no effect on the trypsin-induced relaxation. These results suggest that trypsin increases [Ca 2+ ] i in the endothelial cells through SKF-96365-insensitive Ca 2+ channels and regulates the release of NO, which results in relaxation of the rat aorta. KEY WORDS: cytosolic calcium level, endothelium derived relaxation, trypsin.

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Protease-Activated Receptor-2 Involvement in Hypotension in Normal and Endotoxemic Rats In Vivo

Cited by 100 publications

References 20 publications

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

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

Delayed Onset of Inflammation in Protease-Activated Receptor-2-Deficient Mice

Effects of Trypsin on Cytosolic Calcium Levels in the Rat Aortic Endothelium

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