Vol 5: Pharmacological evidence of bradykinin regeneration from extended sequences that behave as peptidase-activated B2 receptor agonists.Report as inadecuate



 Vol 5: Pharmacological evidence of bradykinin regeneration from extended sequences that behave as peptidase-activated B2 receptor agonists.


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This article is from Frontiers in Pharmacology, volume 5.AbstractWhile bradykinin BK is known to be degraded by angiotensin converting enzyme ACE, we have recently discovered that Met-Lys-BK-Ser-Ser is paradoxically activated by ACE. We designed and evaluated additional -prodrug- peptides extended around the BK sequence as potential ligands that could be locally activated by vascular or blood plasma peptidases. BK regeneration was estimated using the contractility of the human umbilical vein as model of vascular functions mediated by endogenous B2 receptors B2Rs and the endocytosis of the fusion protein B2R-green fluorescent protein B2R-GFP expressed in Human Embryonic Kidney 293 cells. Of three BK sequences extended by a C-terminal dipeptide, BK-His-Leu had the most desirable profile, exhibiting little direct affinity for the receptor but a significant one for ACE as shown by competition of 3HBK binding to B2R-GFP or of 3Henalaprilat to recombinant ACE, respectively. The potency of the contractile effect of this analog on the vein was reduced 18-fold by the ACE inhibitor enalaprilat, pharmacologically evidencing BK regeneration in situ. BK-Arg, a potential substrate of arginine carboxypeptidases, had a low affinity for B2Rs and its potency as a contractile agent was reduced 15-fold by tissue treatment with an inhibitor of these enzymes, Plummer’s inhibitor. B2R-GFP internalization in response to 100 nM of the extended peptides recapitulated these findings, as enalaprilat selectively inhibited the effect of BK-His-Leu and Plummer’s inhibitor, that of BK-Arg. The two peptidase inhibitors did not affect BK-induced effects in either assay. The novel C-terminally extended BKs had no or very little affinity for the kinin B1 receptor competition of 3HLys-des-Arg9-BK binding. The feasibility of peptidase-activated B2R agonists is illustrated by C-terminal extensions of the BK sequence.



Author: Charest-Morin, Xavier; Roy, Caroline; Fortin, Emile-Jacques; Bouthillier, Johanne; Marceau, Francois

Source: https://archive.org/







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