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.

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