V1a Agonists in Vasodilatory Shock: From Bedside to Bench, and Back

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V1a Agonists in Vasodilatory Shock: From Bedside to Bench, and Back

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Title: V1a Agonists in Vasodilatory Shock: From Bedside to Bench, and Back
Author/Creator: Landry, D W | Rivière, P | Schteingart, C | Laporte, R | Wisniewski, K | Croston, G | Alagarsamy, S | Cantor, P | McAnulty, P | Al-Shubarj, A | Oliver, J A | Macdonald, J | Russell, J | Walley, K R | Curry, F | Lenz, J | Traber, D L | Enkhbaatar, P | Radermacher, P | Calzia, E
Description: The peptide hormone vasopressin is best known for its anti-diuretic action mediated by V2-receptors present on the collecting duct on the kidney. But as the name suggests vasopressin, at very low concentrations (0-5 pg/mL), is also a vasopressor hormone and in this capacity it acts through V1a–receptors present on vascular smooth muscle. In vitro, vasopressin is 100-fold more potent as a vasopressor than the catecholamine norepinephrine but in vivo vasopressin has little effect on blood pressure at concentrations of hundreds of pg/ mL. However, we (DWL) discovered that in vasodilatory shock, vasopressin is transformed into an exquisitely potent vasopressor that decreases the requirement for catecholamine pressors. Low blood pressure and endotoxemia raise plasma vasopressin levels in experimental animals to more than 300 pg/mL but we (DWL) discovered that patients in septic shock are vasopressin defi cient with circulating levels of 0-5 pg/mL. Numerous investigators have confi rmed vasopressin defi ciency and pressor hypersensitivity to be hallmarks of septic shock. The recently reported VASST trial further suggests that vasopressin replacement could be benefi cial for patients with moderately severe septic shock. However questions remain as to whether the natural hormone, a non-specifi c V1a/V2-receptor agonist, is the ideal agent for the treatment of septic shock. Normal subjects, but not patients with congenital nephrogenic diabetes insipidus also lack functioning V2- receptors, experience a decrease in blood pressure in response to administration of a V2-selective agonist, consistent with fi ndings that the V2-receptor mediates vasodilatation. Further, infusion of vasopressin itself into the brachial artery results in forearm vasodilatation indicating that V2 activity can dominate V1a in selected vascular beds. Thus, we (Ferring) sought to develop V1a selective agonists and FE 202158 was identified from a focused peptide library. FE 202158 demonstrated excellent selectivity for human V1a –R over V1b –R hOTR and hV2R: 1/142, 1/440 and 1/1107, respectively; and in contrast to that of vasopressin: 1, 1/18, 1/92, 5. (Figure 1) FE 202158 was also potent and selective across multiple species of interest for preclinical trials including rat, dog, sheep and pig. (Figure 2) In studies of pseudomonas sepsis in pig, and platelet activating factor administration as a model of septic shock/anaphylactic shock in rat, FE 202158 was a potent vasopressor agent at concentrations that mimicked low dose hormone replacement with vasopressin. Various clinically signifi cant benefi ts with respect to fl uid balance were identifi ed.
Relation: 3rd Annual Peptide Therapeutics Symposium, San Diego, United States 24 October, 2008
Relation: Program and Proceedings: 3rd Annual Peptide Therapeutics Symposium / pp.12
Relation: http://www.peptidetherapeutics.org/PTS08_proceedings-final.pdf
Year: 2008
Subject: FoR 0601 (Biochemistry and Cell Biology)

Collection(s): Research Publications
Resource Type: Conference Abstract

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