Vasopressin antagonist inhibition of clotting factor release in the rhesus monkey (Macaca mulatta).
The antidiuretic (V2) agonist, dDAVP, stimulates release of the clotting factors von Willebrand factor (vWF) and factor VIIIc (FVIIIc) in humans. The objective of these studies was to identify and characterize dDAVP stimulation of clotting factor release in pentobarbital-anesthetized rhesus monkeys using V2 receptor agonists (dDAVP, SK&F 101926, SK&F 104146, SK&F 104244) and a V2 receptor antagonist (SK&F 105494) given i.v. dDAVP (3.0 micrograms/kg) stimulated release of vWF, FVIIIc and renin and was associated with tachycardia and blood pressure-lowering activity. The V2 receptor antagonist, SK&F 105494 (30 micrograms/kg, i.v.), had no effect on clotting factor release, heart rate or blood pressure, but prevented dDAVP stimulation of clotting factor release and tachycardia. The V2 agonists SK&F 101926, SK&F 104146 and SK&F 104244 did not stimulate clotting factor release, blood pressure, heart rate or plasma renin activity in this species at the doses tested. Thus, the rhesus monkey is a nonhuman primate species in which dDAVP stimulation of FVIIIc and vWF occurs. The results support the hypothesis that dDAVP stimulation of clotting factor release is mediated by a low-affinity, V2-like receptor mechanism. The tachycardia and renin release associated with dDAVP administration are most likely secondary to vasodilation, also mediated by a V2-like mechanism.
Kinter
L B
LB
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
McConnell
I
I
Goodwin
B T
BT
Campbell
S
S
Huffman
W F
WF
Arthus
M F
MF
Lonergan
M
M
Bichet
D G
DG
D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D005169:Factor VIII / Q000378:metabolism*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D014667:Vasopressins / Q000037:antagonists & inhibitors*; D014841:von Willebrand Factor / Q000378:metabolism*
D014841:von Willebrand Factor; D014667:Vasopressins; D001127:Arginine Vasopressin; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin