Association between Kinin B₁ Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules

Using intravital microscopy, we examined the role played by B₁ receptors in leukocyte trafficking across mouse mesenteric postcapillary venules in vivo. B₁ receptor blockade attenuated interleukin (IL)-1β–induced (5 ng intraperitoneally, 2 h) leukocyte–endothelial cell interactions and leukocyte emigration (∼50% reduction). The B₁ receptor agonist des-Arg⁹bradykinin (DABK), although inactive in saline- or IL-8–treated mice, caused marked neutrophil rolling, adhesion, and emigration 24 h after challenge with IL-1β (when the cellular response to IL-1β had subsided). Reverse transcriptase polymerase chain reaction and Western blot revealed a temporal association between the DABK-induced response and upregulation of mesenteric B₁ receptor mRNA and de novo protein expression after IL-1β treatment. DABK-induced leukocyte trafficking was antagonized by the B₁ receptor antagonist des-arg¹⁰HOE 140 but not by the B₂ receptor antagonist HOE 140. Similarly, DABK effects were maintained in B₂ receptor knockout mice. The DABK-induced responses involved the release of neuropeptides from C fibers, as capsaicin treatment inhibited the responses. Treatment with the neurokinin (NK)₁ and NK₃ receptor antagonists attenuated the responses, whereas NK₂, calcitonin gene-related peptide, or platelet-activating factor receptor antagonists had no effect. Substance P caused leukocyte recruitment that, similar to DABK, was inhibited by NK₁ and NK₃ receptor blockade. Mast cell depletion using compound 48/80 reduced DABK-induced leukocyte trafficking, and DABK treatment was shown histologically to induce mast cell degranulation. DABK-induced trafficking was inhibited by histamine H₁ receptor blockade. Our findings provide clear evidence that B₁ receptors play an important role in the mediation of leukocyte–endothelial cell interactions in postcapillary venules, leading to leukocyte recruitment during an inflammatory response. This involves activation of C fibers and mast cells, release of substance P and histamine, and stimulation of NK₁, NK₃, and H₁ receptors.