Vol. 282, Issue 2, 597-602, 1997

V₂ Receptor Antagonism of DDAVP-Induced Release of Hemostasis Factors in Conscious Dogs

A. Bernat, P. Hoffmann, A. Dumas, C. Serradeil-Le Gal, D. Raufaste and J. M. Herbert

Sanofi Recherche, Toulouse, France

The synthetic arginine vasopressin (AVP) analog 1-desamino-8-D-arginine vasopressin (DDAVP) is used in a variety of hemorrhagic disorders. The present experiments were designed to further characterize the mechanism of DDAVP-induced release of hemostasis factors. The [³H]AVP-labeled AVP receptor in canine renomedullary membranes exhibited an AVP V₂ profile because the V₂ receptor agonist DDAVP displayed similar subnanomolar affinities as the natural hormone AVP, whereas the two selective V_1a compounds SR 49059 and d(CH₂)₅Tyr(Me)-AVP as well as the selective V_1b agonist D-Pal and oxytocin were much less potent. The rank order of the binding affinities of three V₂ receptor antagonists was SR 121463 (a newly described selective V₂ receptor antagonist) > OPC 31260  d(CH₂)₅D-lle²,lle⁴AVP. In conscious dogs, DDAVP (0.1-1 µg/kg IV) caused a dose-related increase (maximum, 43-52% at 30 min) in plasma levels of factor VIII (FVIII), von Willebrand factor (vWF) and tissue-type plasminogen activator (t-PA), but not in levels of plasminogen activator inhibitor-1. A DDAVP-induced hemostasis factor release was also observed in bilaterally nephrectomized dogs. Pretreatment with SR 121463 inhibited DDAVP-induced (1 µg/kg IV) increases in FVIII, vWF and t-PA plasma levels in a dose-dependent manner (ID₅₀ = 14.0 ± 4.0, 12.4 ± 3.0 and 16.7 ± 1.0 µg/kg IV, respectively). OPC 31260 (300 µg/kg IV) revealed a lower activity than SR 121463, and d(CH₂)₅[D-lle²,lle⁴]AVP (30 µg/kg IV) was without effect on the DDAVP response. Pretreatment with SR 49059 (1 mg/kg IV) and SR 27417 (a platelet-activating factor receptor antagonist) (1 mg/kg IV) had no effect on the DDAVP-induced (1 µg/kg IV) increases in FVIII, vWF and t-PA plasma levels. The present results, therefore, strongly suggest that the effect of DDAVP on hemostasis factors occurs via a specific interaction with extrarenal V₂ receptors.