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 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.