title: Unique gradual and sustained vasodilator response to substance P in the rabbit knee joint.
abstract: 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 NK(1) 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 NK(1) receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-m ethyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide (FK888) and the NK(2) receptor antagonist (S)-N-methyl-N-[4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl] benzamide (SR48968), at 2x1 nmol and 2x10 nmol, had no effect on the substance P-induced response, which however was reduced by pyrilamine, cimetidine, and flurbiprofen (all at 2x10 nmol). N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-D-arginine methyl ester (D-NAME), both at 2x100 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 NK(1) or NK(2) 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 the 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.
authors.affiliation: Department of Pharmacology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, People's Republic of China. francislam@cuhk.edu.hk
authors.forename: F F
authors.initials: FF
authors.lastname: Lam
authors.forename: A L
authors.initials: AL
authors.lastname: Yip
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005480:Flurbiprofen / Q000494:pharmacology; D006614:Hindlimb; D007211:Indoles / Q000494:pharmacology; D007270:Injections, Intra-Articular; D007596:Joints / Q000098:blood supply* / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; D004151:Dipeptides; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C078949:FK 888; D013373:Substance P; D005070:Evans Blue; D005480:Flurbiprofen; C073839:SR 48968