Combined effect of bradykinin B2 and neurokinin-1 receptor activation on endothelial cell proliferation in acute synovitis.

During acute synovitis, early angiogenesis may enhance inflammation by facilitating edema formation and cellular infiltration. We have investigated the in vivo modulation by bradykinin of neurally enhanced early angiogenesis in rat models of knee synovitis. The increased endothelial cell proliferation that was observed 24 h after intra-articular injection of substance P (10 nmols) was completely blocked by either NK1 or B-2 receptor antagonists (SR140333 or FR172357, respectively). In mild synovitis induced by 0.03% Carrageenan, but not in naive animals, injection of bradykinin (100 nmols) increased endothelial cell proliferation. In moderate synovitis induced by 3% kaolin and 3% carrageenan, the combined blockade of both NK1 and B-2 receptors inhibited 64% of the synovitis-enhanced endothelial cell proliferation. Synovitis-enhanced endothelial cell proliferation was also inhibited by the B-2 receptor antagonist alone (27%) but not by the NK1 receptor antagonist alone. B-1 receptor agonist (des-Arg(9)-bradykinin) and antagonist (SR240612A) did not significantly modulate endothelial cell proliferation. B-2 receptor mRNA was constitutively expressed in both mild and moderate inflammation, whereas B-1 mRNA production was induced in the moderate inflammation model. These findings demonstrate that substance P and bradykinin can act on NK1 and B-2 receptors, respectively, to promote endothelial cell proliferation in acute synovitis.