Modulation of synovial blood flow by the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP((8-37))

Abstract

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((8-37)) (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.