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Title: The role of alpha CGRP in L-NAME-induced hypertension
Author: Argunhan, Fulye
ISNI:       0000 0004 9351 2821
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Calcitonin gene-related peptide (CGRP) is primarily localised and released from sensory nerves. It is a potent vasodilator neuropeptide with cardioprotective effects. The most common cardiovascular-relevant form is αCGRP. It signals via the CGRP receptor which is composed of the G-protein linked calcitonin like receptor (CLR) and an associated receptor associated modified protein (RAMP1); both of which are essential for function. There remains an unmet need in the treatment of cardiovascular disease and we hypothesised that CGRP acts via the CGRP receptor in an endothelial-independent manner to mediate its vasodilator and protective effects in vivo. The aim was to investigate the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension model in adult C57BL/6 wild-type (WT) and global αCGRP knock-out (KO) mice, which have similar baseline haemodynamics. The results showed that: i) αCGRP KO mice develop exacerbated hypertension in the presence of L-NAME, compared with WT mice and this was associated with adverse cardiovascular remodelling. This indicates that CGRP acts, at least in part, independently of endothelial-derived nitric oxide. ii) use of BIBN 4096 BS, a selective CGRP receptor antagonist supported these results, demonstrating the essential role of the CGRP receptor. No evidence was found for the involvement of a second proposed CGRP receptor (CTR/RAMP1). iii) RAMP1, but not CLR protein, from the CGRP receptor complex, was upregulated with L-NAME treatment. iv) αCGRP infusion reversed L-NAME-induced hypertension in αCGRP KO mice to the normotensive range. v) studies into the vascular site of CGRP’s protective action indicated that the mesenteric vessels, rather than the skin, play an important role in regulating the protective effect of CGRP; specifically, in first order mesenteric arterioles. This study in mice reveals that the therapeutic benefits of αCGRP extends to situations where endothelial dysfunction associated with reduced nitric oxide production exists.
Supervisor: Brain, Susan Diana ; Smith, Alberto Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available