Combined effect of bradykinin B₂and neurokinin‐1 receptor activation on endothelial cell proliferation in acute synovitis.

Abstract

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 B2 receptor antagonists (SR140333 or FR172357, respectively). In mild synovitis induced by 0.03% Carrageenan, but not in naïve 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 B2 receptors inhibited 64% of the synovitis-enhanced endothelial cell proliferation. Synovitis-enhanced endothelial cell proliferation was also inhibited by the B2 receptor antagonist alone (27%) but not by the NK1 receptor antagonist alone. B1 receptor agonist (des-Arg9-bradykinin) and antagonist (SR240612A) did not significantly modulate endothelial cell proliferation. B2 receptor mRNA was constitutively expressed in both mild and moderate inflammation, whereas B1 mRNA production was induced in the moderate inflammation model. These findings demonstrate that substance P and bradykinin can act on NK1 and B2 receptors, respectively, to promote endothelial cell proliferation in acute synovitis.

Peptide Hormone Regulation of Angiogenesis

“…Actually, activation of B1 receptors may be seen as a mechanism to magnify BK actions, since this receptor subtype is normally expressed in the same cell types as the B2 receptor, uses similar signaling pathways but is less vulnerable to desensitization, and mediates the activity of other kinin metabolites (8). Inhibitors of receptors B1 (234,321) and B2 (234,262,489) reduce in vivo angiogenesis and inhibit BK-induced endothelial cell proliferation (366,376) and tube formation (366) in vitro. Notably, BK also stimulates endothelial cell growth and permeability by increasing B2 receptor-mediated VEGF expression in fibroblasts (255,262) and smooth muscle cells (289), whereas the B1 receptor contributes to the proangiogenic action of BK by increasing bFGF synthesis in endothelial cells (137,376,426).…”

Peripheral Neurokinin-1 Receptors Contribute to Kaolin-Induced Acute Monoarthritis in Rats

“…When injected together into the knee joint, kaolin and CGN cause moderate and transient arthritis characterized by a rapid knee swelling that is accompanied by angiogenesis, increased blood flow, leukocyte infiltration, allodynia, and hyperalgesia [11,13,14]. Intraperitoneal injection of kaolin alone induced abdominal pain (constrictions) in rodents and dose-related inflammation when injected intradermally into the rat hindpaw [21,22,23] or dorsal skin [24,25,26].…”

“…In combination with CGN, kaolin causes moderate arthritis, characterized by rapid knee swelling concomitantly with increased blood flow, angiogenesis, allodynia, and both secondary mechanical and thermal hyperalgesia [10,11,12,13,14]. Our previous studies show that intra-articular injection of CGN alone causes knee inflammation and secondary tactile allodynia by triggering a wide inflammatory cascade, including increased NO production and protein oxidation, that may maintain an ongoing state of inflammation in the joint [15,16].…”

Reduction in serum levels of substance P in patients with rheumatoid arthritis by etanercept, a tumor necrosis factor inhibitor

“…The average concentration of substance P in the active stage of RA before treatment with etanercept was significantly higher than that in the moderate stage of RA 4 weeks after treatment with etanercept. Intra-articular injection of substance P has been found to increase the severity of arthritis [21] and to lead to endothelial cell proliferation [22]. Substance P is also known to be present in innervations of the joint synovium [4,23].…”