Background Urocortin 2 and urocortin 3 are endogenous peptides with an

Background Urocortin 2 and urocortin 3 are endogenous peptides with an emerging part in cardiovascular pathophysiology. (test as appropriate (Graph‐Pad Prism GraphPad Software San Diego CA). Significance was taken as 2‐sided test Ucn 2 120 pmol/min versus +10‐minute washout; P=0.04) and thereafter the blood flow gradually returned toward baseline. This was in contrast to the effect seen with urocortin 3 for which the maximum vasodilatory response was immediate (Physique 4A). The offset of vasodilatation was prolonged with both peptides although urocortin 2 took longer than urocortin 3 to return to baseline (Physique 4A). Physique 4. Pharmacodynamics of urocortin 2 (Ucn 2) and urocortin 3 (Ucn 3). A Onset and offset of vasodilatory effect of Ucn 2 (left) and Ucn 3 (right) after infusion Lomeguatrib of highest dose. B Within‐day reproducibility of Ucn 2 (left) and Ucn 3 (right); P=nonsignificant … The vasodilator effects of both peptides appeared to be reproducible within a day with no evidence of tachyphylaxis (2‐way ANOVA P>0.05 for all those; Physique 4B). Endogenous Fibrinolytic Factors Preliminary data showed no effect of urocortin 2 Lomeguatrib or urocortin 3 on endothelial release of tissue plasminogen activator and plasminogen activator inhibitor‐1 (data on file). Mechanism of Vasodilatation Baseline forearm arterial blood flow was unaffected by oral aspirin or intra‐arterial fluconazole and the coinfusion of SNP restored baseline GluN1 blood flow during L‐NMMA administration (2‐way ANOVA P>0.05 for all those). Inhibition of nitric oxide synthase reduced arterial vasodilatation to material P and urocortin 2 (2‐way ANOVA P≤0.001 for both) but had no apparent effect on urocortin 3-induced vasodilatation (2‐way ANOVA P=0.36). Neither inhibition of cyclo‐oxygenase with aspirin nor cytochrome P450 metabolites of arachidonic acid with fluconazole affected the vasodilatation induced by the urocortins or material P (2‐way ANOVA P>0.05 for all those; data on file). In the presence of all 3 inhibitors material P- urocortin 2- and urocortin 3-induced vasodilatation was further attenuated (2‐way ANOVA P<0.001 for all those) but not completely abolished. Combined inhibition of cyclo‐oxygenase nitric oxide synthase and cytochrome P450 metabolites of arachidonic acid produced a greater reduction in vasodilatation than the nitric oxide clamp alone (2‐way ANOVA Lomeguatrib P≤0.005 for urocortins 2 and 3; Physique 5). Physique 5. Vasomotor effects of inhibition of endothelial nitric oxide synthase cycloxygenase and cytochrome P450 metabolites of arachidonic acid on urocortin 2- urocortin 3- and material P-mediated vasodilatation. Open circle placebo; … Discussion This study represents the first administration in humans of urocortin 3 and demonstrates that both urocortin 2 and urocortin 3 directly evoke potent and prolonged arterial vasodilatation that is at least in part mediated by the endothelium. These findings are of direct relevance not only to our understanding of human cardiovascular physiology but also inform the development of therapies targeting the urocortin system for the treatment of conditions Lomeguatrib such as heart failure. The forearm arterial vasodilator effects of urocortin 2 and urocortin 3 are consistent with data from in vitro3 15 and preclinical19-20 animal studies. However in contrast with existing preclinical data we observed a more marked difference in potency between the 2 peptides. Although preclinical studies have suggested urocortin 2 is usually 10‐fold more potent 21 Wiley et al3 showed equipotency of urocortins 2 and 3 in isolated human internal mammary arterial segments. In contrast here we observed that a 300‐fold‐higher dose of urocortin 3 was required to evoke comparable vasomotor effects in human forearm arterial circulation. This discrepancy underlines the importance of a direct head‐to‐head assessment in vivo in humans without which the extrapolation of preclinical data may be deceptive. Urocortins 2 and 3 are specific agonists at the G‐protein‐coupled CRH‐R2 receptors mediating their effects through a cascade of intracellular signaling pathways including adenyl cyclase cyclic adenosine monophosphate.