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Cytokines, interleukin-1 (IL-I), tumor necrosis factor a, and the neurotransmitter, substance P, have been implicated in the pathogenesis of arthritis because they stimulate synovial cells to secrete prostaglandin E, and collagenase in vitro. We investigated in vivo changes in intraarticular substance P and the degradation of cartilage proteoglycan in response to intraarticular cytokine injections in rabbits. Twenty-four hours after a single injection of 10 ng, 30 ng, or 100 ng of recombinant human &la (rHuIL-la) per joint, the mean f SEM levels of substance P detected in the cell-free joint lavage fluid were 250 & 67 fmoles, 480 2 60 fmoles, and 530 & 130 fmoles (n = 4-9, respectively. The level of substance P in the contralateral knees injected with diluent was 58 -c 8 fmoles (n = 12). The level of substance P had increased by 2 hours after IL-1 injection and remained elevated in the joint 48 hours after injection. Cytokineinduced proteoglycan depletion was also time-and dosedependent. Proteoglycan concentrations in articular cartilage dissected from the weight-bearing condyles were calculated as the ratio of sulfated glycosaminoglycan measured using 1,9-dimethyImethylene blue:hydroxyproline. After 48 hours, 10 ng, 30 ng, or 100 ng of rHuIL-la per joint decreased proteoglycan levels by 9 f 4%, 14 f 4%, and 21 2 3% (n = a), respectively. Likewise, the injection of recombinant human

Cartilage degeneration in osteoarthritis is initiated by a loss of proteoglycan. Intra-articular injection of papain causes a reversible loss of proteoglycan in rabbit knees. Rabbits were scanned with magnetic resonance imaging (MRI), using a 1.5T Signa superconducting magnet with 3 inch surface coil. Spin echo sequences were performed in the coronal and sagittal planes at 0, 24, 48, and 72 h after intra-articular injection of papain to obtain T1, proton density, and T2-weighted images. Cartilage proteoglycan content was measured biochemically and histochemically. Reduced articular cartilage thickness in the MR images of papain-treated knees corresponded to changes in cartilage proteoglycan content.

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The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

Intra-articular (i.a.) injection of papain causes a reversible loss of proteoglycan in intact rabbit knees. Twelve rabbits were scanned with magnetic resonance imaging (MRI) at 0, 24, 48 and 72 hours after 5 units of papain i.a. in a 1.5 Tesla Signa with a three inch surface coil using spin echo sequence. Total cartilage thickness in proton density images was 1.08 +/- 0.09 mm prior to papain injection. The magnetic resonance images showed a reduction in articular cartilage thickness in papain-treated rabbit femurs at 24 hours to 0.69 +/- 0.18 mm and partial restoration by 72 hours to 0.77 +/- 0.21 mm.