title: Vascular effects of urocortins 2 and 3 in healthy volunteers.
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.
  
  
  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.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov//. Unique identifier: NCT01096706 and NCT01296607.
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Venkatasubramanian
authors.forename: Megan E
authors.initials: ME
authors.lastname: Griffiths
authors.forename: Steven G
authors.initials: SG
authors.lastname: McLean
authors.forename: Mark R
authors.initials: MR
authors.lastname: Miller
authors.forename: Rosa
authors.initials: R
authors.lastname: Luo
authors.forename: Ninian N
authors.initials: NN
authors.lastname: Lang
authors.forename: David E
authors.initials: DE
authors.lastname: Newby
mesh_terms: D000328:Adult; D016718:Arachidonic Acid / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012606:Scotland; D013373:Substance P / Q000008:administration & dosage; D013997:Time Factors; D054832:Urocortins / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D054832:Urocortins; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D013373:Substance P; D003577:Cytochrome P-450 Enzyme System; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases