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Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers

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...

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Autores principales: Venkatasubramanian, Sowmya, Griffiths, Megan E., McLean, Steven G., Miller, Mark R., Luo, Rosa, Lang, Ninian N., Newby, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603262/
https://www.ncbi.nlm.nih.gov/pubmed/23525432
http://dx.doi.org/10.1161/JAHA.112.004267
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author Venkatasubramanian, Sowmya
Griffiths, Megan E.
McLean, Steven G.
Miller, Mark R.
Luo, Rosa
Lang, Ninian N.
Newby, David E.
author_facet Venkatasubramanian, Sowmya
Griffiths, Megan E.
McLean, Steven G.
Miller, Mark R.
Luo, Rosa
Lang, Ninian N.
Newby, David E.
author_sort Venkatasubramanian, Sowmya
collection PubMed
description 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. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607.
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spelling pubmed-36032622013-03-27 Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers Venkatasubramanian, Sowmya Griffiths, Megan E. McLean, Steven G. Miller, Mark R. Luo, Rosa Lang, Ninian N. Newby, David E. J Am Heart Assoc Original Research 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. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607. Blackwell Publishing Ltd 2013-02-22 /pmc/articles/PMC3603262/ /pubmed/23525432 http://dx.doi.org/10.1161/JAHA.112.004267 Text en © 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by/2.5/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Venkatasubramanian, Sowmya
Griffiths, Megan E.
McLean, Steven G.
Miller, Mark R.
Luo, Rosa
Lang, Ninian N.
Newby, David E.
Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title_full Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title_fullStr Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title_full_unstemmed Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title_short Vascular Effects of Urocortins 2 and 3 in Healthy Volunteers
title_sort vascular effects of urocortins 2 and 3 in healthy volunteers
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603262/
https://www.ncbi.nlm.nih.gov/pubmed/23525432
http://dx.doi.org/10.1161/JAHA.112.004267
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