Tachykinin regulation of basal synovial blood flow.
1. Experiments were performed to investigate the role of endogenously released tachykinins in the regulation of blood flow 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 NK1 receptor antagonist, FK888, nor the selective tachykinin NK2 receptor antagonist, SR48968, significantly influenced synovial blood flow at doses of 10(-12), 10(-10) and 10(-8) mol. However, topical co-administration of these agents produced significant dose-dependent reductions in basal synovial perfusion of 6.3 +/- 4.6 and 12.0 +/- 3.4 and 19.9 +/- 2.6%, respectively; n = 29. The non-selective tachykinin NK1/NK2 receptor antagonist, FK224, also produced significant (at 10(-10) and 10(-8) 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 alpha 1-, alpha 2-adrenoceptor antagonist phenoxybenzamine elicited a 31.3 +/- 6.2% increase in blood flow which was substantially reduced to 10.4 +/- 3.8% by co-administration of the FK888 and SR48968 (both at 10(-8) 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(-8) mol) now produced slight vasodilatation (6.7 +/- 4.6%; n = 9) which did not differ significantly from vehicle treatment. Depletion of tachykinins from sensory nerve fibres by systemic capsaicin administration also resulted in abolition of the vasoconstrictor effect of FK888 and SR48968 (both at 10(-8) 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(-8) mol) again elicited vasoconstriction (48.8 +/- 16.2% reduction in blood flow; n = 4). 6. These results indicate that endogenous tachykinins may be continuously released from sensory fibers innervating the joint. Basal release of tachykinins could therefore be an important physiological influence opposing sympathetic vasoconstrictor tone.
Ferrell
W R
WR
Division of Neuroscience & Biomedical Systems, Institute of Biomedical & Life Sciences, University of Glasgow.
Lockhart
J C
JC
Karimian
S M
SM
D000287:Administration, Topical; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006614:Hindlimb; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007596:Joints / Q000098:blood supply; D017078:Laser-Doppler Flowmetry; D008297:Male; D008854:Microscopy, Electron; D009412:Nerve Fibers / Q000187:drug effects / Q000648:ultrastructure; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D013583:Synovial Membrane / Q000098:blood supply / Q000187:drug effects* / Q000294:innervation / Q000648:ultrastructure; D015320:Tachykinins / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D001549:Benzamides; D004151:Dipeptides; D007211:Indoles; D010456:Peptides, Cyclic; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D018039:Receptors, Tachykinin; D015320:Tachykinins; D010643:Phenoxybenzamine; C075570:FK 224; C078949:FK 888; C073839:SR 48968