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

Abstract

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.

Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans

“…28,29 Although confirming previous observations of PAR-2-mediated venodilatation, 30 we have rather unexpectedly described a dose-dependent venoconstriction with PAR-1 activation. This may be mediated by platelet activation, release of endothelium-derived vasoconstrictors, or a direct effect on venous smooth muscle cells.…”

“…We have not assessed the mechanism of this vasodilatation, but animal and clinical models suggest that this is likely to be endothelium and nitric oxide dependent. 11,30 However, data from animal studies have limited relevance in humans because of the wide species variability in PAR-1 receptor expression and function. The mechanism of PAR-1-induced vasodilatation needs to be addressed in future clinical studies.…”

Elastase-Induced Suppression of Endothelin-Mediated Ca 2+ Entry Mechanisms of Vascular Contraction

“…22 Other studies have shown that activation of PARs causes vasodilation through a nitric oxide-dependent mechanism. 23 Further studies are needed to define the role of integrins and PARs as possible molecular mechanisms by which elastase could inhibit Ca 2ϩ entry into the smooth muscle.…”

Progression of Time-Dependent Changes to the Mechanisms of Vasodilation by Protease-Activated Receptor 2 in Metabolic Syndrome

“…3,4) Protease-activated receptor 2 (PAR2) is expressed on the vascular endothelium, and when it is activated, causes endothelium-dependent vasodilations of a variety of arteries in human and experimental animals via releasing of NO, prostanoids, and endothelium-dependent hyperpolarizing factor (EDHF). [5][6][7] PAR2 is a member of PAR, and it is a class-A G protein-coupled receptor (International Union of Basic and Clinical Pharmacology nomenclature site: http://www.guidetopharmacology.org/nomenclature.jsp). There are four members of the PARs receptor family.…”