The selective V_1a receptor agonist FE 202158 does not cause von Willebrand factor release in sheep unlike arginine vasopressin

Introduction

The mixed V_1a/V₂ receptor agonist arginine vasopressin (AVP) is recommended by the guidelines of the Surviving Sepsis Campaign as an adjunct vasopressor in norepinephrine-resistant septic shock. However, AVP may be procoagulant through V₂ receptor-mediated effects (for example, von Willebrand factor (vWF) release).

Objective

We hypothesized that the selective V_1a receptor agonist FE 202158, which lacks the activity at the V₂ receptor, might not have the procoagulant effects of AVP. This hypothesis was tested by measuring vWF antigen (vWF:Ag) activity in plasma of healthy sheep during administration of either FE 202158, AVP, the selective V₂ receptor agonist desmopressin, or vehicle.

Methods

After measurements of vWF:Ag activity and hemoglobin concentration in blood over a 1-hour baseline period, 24 female sheep were randomly assigned to receive either an intravenous bolus of the selective V₂ receptor agonist desmopressin (1 nmol/kg) or a continuous intravenous infusion of AVP (3 pmol/kg/min), the selective receptor agonist FE 202158 (10 pmol/kg/min) or V_1a vehicle (0.9% NaCl, n = 6 each). The infusion rates were representative of the requirements for the treatment of sepsis-induced vasodilatory hypotension in sheep. vWF:Ag activity and hemoglobin concentration were measured 60, 90 and 120 minutes after initiation of treatment. Because of the V₂ receptor-mediated fluid retention, vWF:Ag activity was corrected for plasma volume changes by calculating the ratio of vWF:Ag activity/hemoglobin concentration (vWF:Ag/Hb). Data are expressed as a percentage of the mean baseline value and presented as mean ± SEM.

Results

Whereas there were no significant changes in vWF:Ag/Hb in vehicle-treated animals over time, desmopressin and AVP caused an immediate increase in vWF:Ag/Hb after 60 minutes (129 ± 6% and 121 ± 2% of baseline (100%), respectively; P < 0.01 each). At each time point during the 120-minute study period, vWF:Ag/Hb was significantly higher in desmo-pressin-treated and AVP-treated animals than in vehicle-treated animals (P < 0.001 each). In contrast, there was no significant difference between FE 202158-treated and vehicle-treated animals (P = 0.225). Notably, vWF:Ag/Hb in the FE 202158 group (maximum 108 ± 2% at 120 minutes) was significantly lower than the AVP group (maximum 123 ± 2% at 60 minutes; P ≤ 0.005) and the desmopressin group (maximum 138 ± 6% at 120 minutes; P < 0.001) at every time point.

Conclusion

Unlike AVP, the selective V_1a receptor agonist FE 202158 did not increase vWF:Ag/Hb ratios in plasma compared with vehicle-treated animals. Therefore, a selective V_1a receptor agonist such as FE 202158 might be superior to AVP or other mixed V_1a/V₂ receptor agonists under conditions that produce activation of the coagulation system, such as severe sepsis and septic shock.