Tachykinin regulation of basal synovial blood flow

Abstract

1 Experiments were performed to investigate the role of endogenously released tachykinins in the regulation of blood¯ow to the rat knee joint. Synovial perfusion was assessed by laser Doppler perfusion imaging, which permitted spatial measurement of relative changes in perfusion from control (pre drug administration), expressed as the percentage change. Most experiments were performed on the exposed medial aspect of the knee joint capsule. 2 Neither the selective tachykinin NK 1 receptor antagonist, FK888, nor the selective tachykinin NK 2 receptor antagonist, SR48968, signi®cantly in¯uenced synovial blood¯ow at doses of 10 712 , 10 710 and 10 78 mol. However, topical co-administration of these agents produced signi®cant dose-dependent reductions in basal synovial perfusion of 6.3+4.6, 12.0+3.4 and 19.9+2.6%, respectively; n=29. The non-selective tachykinin NK 1 /NK 2 receptor antagonist, FK224, also produced signi®cant (at 10 710 and 10 78 mol), but less potent, reductions in perfusion of 5.3+4.0, 8.4+2.2 and 5.9+2.8%, respectively; n=25. 3 Topical administration of the a 1 -, a 2 -adrenoceptor antagonist phenoxybenzamine elicited a 31.3+6.2% increase in blood¯ow which was substantially reduced to 10.4+3.8% by co-administration of the FK888 and SR48968 (both at 10 78 mol; n=8 ± 13), suggesting that normally there is sympathetic vasoconstrictor`tone' which is opposed by the vasodilator action of endogenous tachykinins. 4 One week after surgical interruption of the nerve supply to the knee joint, co-administration of FK888 and SR48968 (both at 10 78 mol) now produced slight vasodilatation (6.7+4.6%; n=9) which did not di er signi®cantly from vehicle treatment. Depletion of tachykinins from sensory nerve ®bres by systemic capsaicin administration also resulted in abolition of the vasoconstrictor e ect of FK888 and SR48968 (both at 10 78 mol), with these agents only producing a slight vasodilatation (2.5+5.3%; n=6). 5 By use of a near infra-red laser source it was possible to image knee joint perfusion transcutaneously, the overlying skin being left intact. In this more physiological situation, close intra-arterial injection of the combination of FK888 and SR48968 (both at 10 78 mol) again elicited vasoconstriction (48.8+16.2% reduction in blood¯ow; n=4). 6 These results indicate that endogenous tachykinins may be continuously released from sensory ®bres innervating the joint. Basal release of tachykinins could therefore be an important physiological in¯uence opposing sympathetic vasoconstrictor tone.

The role of joint nerves and mast cells in the alteration of vasoactive intestinal peptide (VIP) sensitivity during inflammation progression in rats

“…Interestingly, topical application of VIP 6–28 alone to normal knees caused a mild but significant decrease in synovial blood flow indicative of tonic VIP release under basal conditions. The function of this basal VIP release is probably to partially offset sympathetic vasoconstrictor tone in synovial blood vessels as has been found with other dilator neuropeptides (Ferrell et al ., 1997; McMurdo et al ., 1997; McDougall et al ., 1999).…”

“…The skin wound was closed with Vetbond skin glue (3M, St Paul, MN, U.S.A.), and these animals were allowed to recover for 1 week. This period of time has previously been found to ensure complete degeneration of almost all articular nerves in the rat knee (Ferrell et al ., 1997). On the day of experimentation, acute kaolin/carrageenan inflammation was induced in the denervated joint.…”

Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint)

“…Synovial inflammatory hyperaemia was quantified using transcutaneous laser Doppler imaging (Lisca, Sweden) to assess synovial blood flow. 2 The sensitivity of laser Doppler in assessing synovial perfusion transcutaneously has been previously confirmed in both animal 2 and human joints. 1 The depilated intact knee joints of deeply anaesthetised (Sigma UK; 1.6 g/kg urethane intraperitoneally) male Wistar rats (n = 4) were scanned after ''sham denervation'' (surgical skin incision but nerve left intact) and intra-articular injection of 2% l-carrageenan and 4% kaolin (wt/vol; Sigma).…”

Bone Blood Flow and Vascular Reactivity

“…results] suggest that inhibition of alpha-adrenergic receptors causes a significant decrease in vascular resistance within the intact tibia of anesthetized rats. Using the same pharmacological approach, Ferrell and colleagues determined that endogenous norepinephrine regulates blood flow to the synovium of the rat knee joint [Ferrell et al, 1997]. Thus, norepinephrine, released from the adrenal gland or sympathetic nerves, appears to play an important role to control flow to bone and joint structures by actively constricting resistance arterioles.…”