Unique gradual and sustained vasodilator response to substance P in the rabbit knee joint

The effects of substance P on blood flow, plasma extravasation, and knee joint sizes in the rabbit were investigated. Topical bolus application of substance P (1 nmol) onto the exposed rabbit knee joint capsule increased its blood flow from 15 min onwards and reached a peak of 46% at 90 min compared to saline administration. However, administration by the same route and the same dose of the NK1 receptor agonist [Sar(9), Met (O-2)(11)]substance P produced no change on the knee joint blood flow compared to the saline control. The NK1 receptor antagonist N-2-[(4 R)-4-hydroxy-1-(1-methyl-1 H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenylmethy]-3-(2-naphrhyl)-L-alaninamide (FK888) and the NK2 receptor antagonist ( S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl] benzamide (SR48968), at 2 x 1 nmol and 2 x 10 nmol, had no effect on the substance P-induced response, which however was reduced by pyrilamine, cimetidine, and flurbiprofen (all at 2 x 10 nmol). N-G-nitro-L-arginine methyl ester (L-NAME) and N-G-nitro-D-arginine methyl ester (D-NAME), both at 2 x 100 nmol, did not significantly affect the substance P-induced response. Unilateral intra-articular administration of substance P (1 nmol) into synovial cavities of the rabbit knee joint increased basal blood flow of the ipsilateral joint at 4 h post-injection, and bilateral increase of basal blood flow was observed at 24 h. Plasma extravasation was significantly higher in the substance P-injected knee compared to the contralateral saline-injected knee at 4 h after intra-articular administrations, but not at 24 h. Knee joint sizes were not affected at both time points. The present study is the first to demonstrate that substance P possesses a gradual and persistent vasorelaxant action in the rabbit knee joint. This novel action of substance P is not mediated by NK1 or NK2 receptors, but involves histamine and prostaglandins. The degree of plasma extravasation elicited by substance P in the rabbit knee joint is small and short-lived, and with no concurrent oedema of me joint. These results suggest that substance P can evoke acute inflammatory responses in the rabbit knee joint, but on its own, it is unlikely to cause chronic joint inflammation in this species. (C) 2000 Elsevier Science B.V. All rights reserved.