Gray, David William; (1992) An investigation into the signal transduction pathways mediating calcitonin gene-related peptide-induced vasorelaxation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Calcitonin gene-related peptide (CGRP) is a vasodilator, having at least two mechanisms of eliciting vasorelaxation, these being dependent on the presence of an intact endothelium in some tissues, but independent in others. The work presented in this thesis is an attempt to clarify the signal transduction pathways mediating CGRP vasorelaxation. Results presented show that CGRP acts in an endothelium-dependent manner in rat thoracic aortic rings via a CGRP(8.37)-insensitive subtype of receptor. The pharmacological profile of inhibition e.g. sensitivity to haemoglobin, methylene blue and the nitric oxide synthase inhibitors but not cyclo-oxygenase inhibitors, sodium/potassium ATPase inhibitors or ATP-sensitive potassium channel blockers, indicates that CGRP and acetylcholine release nitric oxide as their endothelium-derived relaxant factor (EDRF). While both vasodilators increase cyclic GMP levels, CGRP, in contrast to acetylcholine, also causes elevations in cyclic AMP. The elevation in cyclic GMP is probably a result of the release of nitric oxide, but the role of the cyclic AMP required further clarification. Evidence is given indicating that CGRP may belong to a class of drugs, including β-adrenoreceptor agonists and forskolin, which are capable of stimulating nitric oxide synthase by elevating cyclic AMP levels. The endothelium-independent relaxations induced by CGRP in the pig coronary artery are mediated by a CGRP(8.37)-sensitive subtype of receptor and are associated with selective rises in cyclic AMP. In summary the endothelium-dependent and -independent vasorelaxant actions of CGRP in the tissues studied appear to be mediated by two different receptor subtypes. While both receptors appear to be linked to activation of adenylate cyclase, the endothelium-dependent mechanism involves activation of nitric oxide synthase, release of nitric oxide, stimulation of guanylate cyclase and subsequent relaxation. The endothelium-independent mechanism only involves activation of adenylate cyclase and not guanylate cyclase.

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