The selective V1a receptor agonist FE 202158 does not cause von Willebrand factor release in sheep unlike arginine vasopressin
© BioMed Central Ltd 2009
Published: 11 November 2009
The mixed V1a/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).
We hypothesized that the selective V1a 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.
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 V1a 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.
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.
Unlike AVP, the selective V1a receptor agonist FE 202158 did not increase vWF:Ag/Hb ratios in plasma compared with vehicle-treated animals. Therefore, a selective V1a receptor agonist such as FE 202158 might be superior to AVP or other mixed V1a/V2 receptor agonists under conditions that produce activation of the coagulation system, such as severe sepsis and septic shock.