Modulation of synovial blood flow by the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8-37).
1. The effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP(8-37) on blood flow in the knee joint of the anaesthetized rat was investigated. 2. Synovial blood flow in both exposed and intact, skin-covered knees was measured by laser Doppler perfusion imaging. 3. Topical application of CGRP(8-37) caused a dose-dependent fall in synovial blood flow in the exposed knee joint of the rat. At low (1.5 nmol) doses of CGRP(8-37) there was no significant effect on synovial blood flow. In rats treated with 7.5 nmol CGRP(8-37) there was a fall in synovial blood flow (maximum effect at 10 min: -28.8 +/- 4.6%; n=7), which returned to resting levels within 30 min. The highest dose (15 nmol) of antagonist used in this study caused a marked (maximum at 10 min: -35.6 +/- 9.3%; n=8), and prolonged (up to 30 min) fall in blood flow. 4. Ten days after surgical denervation, CGRP(9-37) (15 nmol, topical) had no significant effect on blood flow in the rat exposed knee joint (change in flux at 10 min: -5.1+/-3.6%; n=4). This suggests that CGRP(8-37) acts selectively to antagonize the actions of a neurally derived product, probably CGRP, on the rat synovial vasculature. 5. In skin-covered knee joints, intra-articular injection of CGRP(8-37) (15 nmol; bolus) elicited a significant fall in synovial blood flow (maximum effect at 10 min: -15.5 +/- 5.8%; n=6). 6. CGRP (0.01, 0.1 or 1.0 nmol; topical) caused a dose-dependent increase in exposed knee joint blood flow, which was attenuated by co-administration of 1.5 nmol CGRP(8-37). For example, 1 nmol CGRP elicited a peak increase in flux at 10 min of 94.7 +/- 31.8% (n=8) and 28.8 +/- 8.9% (n=7) in the absence and presence of CGRP(8-37), respectively. The vasodilator responses induced by acetylcholine (ACh) (10 nmol, topical; n=4-5) or sodium nitroprusside (SNP) (10 nmol, topical; n=4-5) were unaltered in the presence of CGRP(8-37) (1.5 nmol, topical). 7. Thus, the CGRP receptor antagonist CGRP(8-37) elicits vasoconstriction in the rat synovium. This suggests that the endogenous, basal release of CGRP may play a physiological role in the regulation of blood flow in the rat knee joint.
McMurdo
L
L
Institute of Biomedical & Life Sciences, University of Glasgow.
Lockhart
J C
JC
Ferrell
W R
WR
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013583:Synovial Membrane / Q000098:blood supply*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide