V-2 RECEPTOR ANTAGONISM OF DDAVP-INDUCED RELEASE OF HEMOSTASIS FACTORS IN CONSCIOUS DOGS

The synthetic arginine vasopressin (AVP) analog 1-desamino-8-D-arginin e vasopressin (DDAVP) is used in a variety of hemorrhagic disorders. T he present experiments were designed to further characterize the mecha nism of DDAVP-induced release of hemostasis factors. The [H-3]AVP-labe led AVP receptor in canine renomedullary membranes exhibited an AVP V- 2 profile because the V-2 receptor agonist DDAVP displayed similar sub nanomolar affinities as the natural hormone AVP, whereas the two selec tive V-1a compounds SR 49059 and d(CH2)(5)Tyr(Me)-AVP as well as the s elective V-1b agonist D-Pal and oxytocin were much less potent. The ra nk order of the binding affinities of three V-2 receptor antagonists w as SR 121463 (a newly described selective V-2 receptor antagonist) > O PC 31260 much greater than d(CH2)(5)D-Ile(2),Ile(4)AVP. In conscious d ogs, DDAVP (0.1-1 mu g/kg IV) caused a dose-related increase (maximum, 43-52% at 30 min) in plasma levels of factor VIII (FVIII), von Willeb rand factor (vWF) and tissue-type plasminogen activator (t-PA), but no t in levels of plasminogen activator inhibitor-1. A DDAVP-induced hemo stasis factor release was also observed in bilaterally nephrectomized dogs. Pretreatment with SR 121463 inhibited DDAVP-induced (1 mu g/kg I V) 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 mu g/kg IV, respectively). OPC 31260 (300 mu g/kg IV) revealed a lower activity t han SR 121463, and d(CH2)(5)[D-Ile(2),Ile(4)]AVP (30 mu g/kg IV) was w ithout effect on the DDAVP response. Pretreatment with SR 49059(1 mg/k g IV) and SR 27417 (a platelet-activating factor receptor antagonist) (1 mg/kg IV) had no effect on the DDAVP-induced (1 mu g/kg IV) increas es in FVIII, vWF and t-PA plasma levels. The present results, therefor e, strongly suggest that the effect of DDAVP on hemostasis factors occ urs via a specific interaction with extrarenal V-2 receptors.