The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

Abstract

Objective To determine if the selective vasopressin type 1a receptor (V1aR) agonist selepressin (FE 202158) is as effective as the mixed V1a/V2 receptor (V1aR/V2R) agonist vasopressor hormone arginine vasopressin (AVP) when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. Design Prospective, randomized, controlled laboratory experiment. Setting University animal research facility. Subjects Forty-five chronically instrumented sheep. Interventions Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure (MAP) fell by > 10 mm Hg from baseline levels, a continuous i.v. infusion of AVP or selepressin was titrated to raise and maintain MAP within 10 mm Hg of baseline. Effects of combination treatment of selepressin with the selective V2R agonist desmopressin were similarly investigated. Measurements and Main Results In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index (SVRI) decreased by ~50%, and ~7 L of fluid were retained over 24 h; this fluid accumulation was partially reduced by AVP and almost completely blocked by selepressin; combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to AVP treatment. Conclusions Resuscitation with the selective V1aR agonist selepressin blocked vascular leak more effectively than the mixed V1aR/V2R agonist AVP because of its lack of agonist activity at the V2R.

Blood cells and endothelial barrier function

“…1,170 Some of these agents (e.g, sphingosine-1-phosphate, activated protein C) appear to act on the barrier to stabilize both the junctions and the cytoskeleton, while other agents target either specific receptors for known potent barrier-altering agents (e.g., VEGF, vasopressin type 1a receptor) or act to interfere with key signaling molecules that promote changes in the junction and/or cytoskeleton to produce a hyperpermeability state (e.g, protein kinase C and RhoA inhibitors). 1,170,171 While these strategies hold promise, additional work is needed to translate the existing knowledge on endothelial barrier regulation to the development of a therapeutic agent that can be routinely used to protect or enhance endothelial barrier function.…”

Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy

“…Increased vascular leak and endothelial permeability are common in septic shock. At least one new vasopressor (selepressin) decreased indirect markers of vascular leak in pre-clinical studies [63] and a Phase II RCT (NCT01000649).…”

Advances in Sepsis Research

“…Selepressin reduced fluid requirements and protected against vascular leak when compared with noradrenalin or vasopressin. 65,66 A preliminary report from a phase 2 trial also suggested a dosedependent limitation of positive fluid balance by selepressin compared with placebo in septic shock. The mechanisms of vascular leakage protection by V 1a agonism in sepsis is not known.…”