Vascular effects of Urocortins 2 and 3 in healthy volunteers

Venkatasubramanian, S., Griffiths, M. E., McLean, S. G., Miller, M. R., Luo, R., Lang, N. N. and Newby, D. E. (2013) Vascular effects of Urocortins 2 and 3 in healthy volunteers. Journal of the American Heart Association, 2(1), e004267. (PMID:23525432) (PMCID:PMC3603262)

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Abstract

Background: Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man. Methods and Results: Eighteen healthy male volunteers (23±4 years) were recruited into a series of double‐blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra‐arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L‐NMMA). Urocortins 2 and 3 evoked arterial vasodilatation (P<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L‐NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all 3 inhibitors, urocortin 2– and urocortin 3–induced vasodilatation was attenuated (P<0.001 for all) to a greater extent than with L‐NMMA alone (P≤0.005). Conclusions: Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits.

Item Type:Articles
Additional Information:Sources of funding: D.E.N., S.G.M., and M.R.M. are supported by the British Heart Foundation (CH/09/002, RG/05/003, PG/10/042/28388).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Newby, Professor David and Lang, Dr Ninian
Authors: Venkatasubramanian, S., Griffiths, M. E., McLean, S. G., Miller, M. R., Luo, R., Lang, N. N., and Newby, D. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American Heart Association
Publisher:Wiley
ISSN:2047-9980
ISSN (Online):2047-9980
Published Online:31 January 2013
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Journal of the American Heart Foundation 2(1):ee004267
Publisher Policy:Reproduced under a Creative Commons license

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