title: Pathophysiology of vascular dysfunction in a rat model of chronic joint inflammation.
abstract: The impact of chronic joint inflammation on articular vascular function in rats was investigated to address whether joint swelling and the associated vascular dysfunction are dependent upon a common prostanoid mechanism. Urinary nitrate/nitrite (NO(x)) and PGE(2) excretion, knee joint diameter and body weight were measured following induction of adjuvant-induced arthritis (AIA). Ten days postinduction of AIA, joint vascular reactivity was assessed by measuring the perfusion response using a laser Doppler imager (LDI) to topical application of acetylcholine (ACh) and sodium nitroprusside (SNP). Four groups were compared: a non-inflamed control group and three AIA groups treated i.p. with vehicle, indomethacin or SC-236 (at equimolar doses). The selective cyclooxygenase-2 (COX-2) inhibitor (SC-236) was used to differentiate between COX-1 and -2-derived prostaglandins. Urinary NO(x) and PGE(2) levels increased substantially during the early phase of AIA but decreased thereafter. Toxicity to indomethacin but not SC-236 was observed, as indicated by a marked decrease in body weight. Joint swelling was similarly attenuated by indomethacin and SC-236 (P= 0.0001 cf. vehicle-treated AIA; n= 5-6 per group), indicating that this is due to COX-2 and not COX-1 inhibition. The AIA-induced changes in urinary NO(x) and PGE(2) were corrected by both COX inhibitors. While vascular reactivity to ACh and SNP was significantly attenuated by AIA (P < 0.002; n= 5-10 per group), the perfusion responses to these vasodilating agents were similar in all three AIA groups, demonstrating that the vascular dysfunction was not corrected by inhibition of either COX-1 or COX-2 enzymes. Furthermore, the attenuation of both ACh and SNP-induced responses in AIA suggest that vascular dysfunction was not exclusively endothelial in nature. In conclusion, the joint swelling and vascular dysfunction associated with AIA appear to be mediated, at least in part, by independent mechanisms. While COX-1/COX-2 inhibition reduced joint swelling, vascular dysfunction in AIA is independent of constitutive or inducible prostanoid mechanisms, and appears not to be solely endothelial-derived, but to involve other components such as the vascular smooth muscle.
authors.affiliation: Biological Sciences, University of Paisley, Paisley PA1 2BE, UK.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Egan
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000652:urine; D004195:Disease Models, Animal; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007719:Knee Joint / Q000098:blood supply* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D008565:Membrane Proteins; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis; D009573:Nitrites / Q000652:urine; D009599:Nitroprusside / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D000096926:Benzenesulfonamides
chemical_list: D000109:Acetylcholine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007213:Indomethacin; D007527:Isoenzymes; D008565:Membrane Proteins; D009566:Nitrates; D009569:Nitric Oxide; D009573:Nitrites; D009599:Nitroprusside; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496513:Ptgs1 protein, rat