Effects of neurohypophyseal hormone analogues on blood clotting factor VIII and fibrinolytic activity in sheep.
The increase in blood clotting factor VIII (antihaemophilic factor, F-VIII) and fibrinolytic activity induced by the administration of neurohypophyseal hormone analogues, was assayed in sheep. Peptides with high selectivity for vasopressin V1, V2 or myometrial oxytocin receptors in the dose range of 0.1-10 micrograms/kg body weight were investigated. The main conclusions are as follows. The time-course of the F-VIII plasma levels following the administration of the peptides was biphasic, with one surge at about 20 min, a rebound phase, and another increase with the maximum at 60-90 min. The time-course of the fibrinolytic response, expressed as biological activity of plasminogen activator in the plasma euglobulin fraction, displayed a single maximum within 60 min. The baseline responses were reached within 90-120 min. Responses were expressed as integrals of the time-concentration curves in a predetermined time range (90-120 min). F-VIII and plasminogen activator enhancing effects seemed to be tightly linked to the specific vasopressin V2 receptor activities. [Val4,D-Arg8]Vasopressin displayed higher plasminogen activator activities than the standard substance, deamino[D-Arg8]vasopressin. The vasotocin analogue [Phe2,Orn8]oxytocin, a specific vasopressin V1 receptor agonist, also displayed high antihaemophilic and fibrinolytic potencies, expressed in terms of ED50 values, but did not reach the same maximal response as vasopressin V2 receptor agonists. Oxytocin and its highly selective uterotonic analogue, [Thr4,Gly7]oxytocin, displayed low antihaemophilic, and virtually no plasminogen activating potencies. Surprisingly, vasopressin V2 and V1V2 receptor antagonists studied in our experiments showed both enhanced F-VIII and fibrinolytic responses. Dose-response curves frequently displayed a decrease of the F-VIII, and sometimes also decreased fibrinolytic responses, at higher peptide doses. Strong decreases of the packed cell volume (haematocrit) and somewhat lower decreases of the total plasma protein concentration were observed shortly after administration of the peptides.
Neuenschwander
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Department of Animal Science, Swiss Federal Institute of Technology, Zürich, Switzerland.
Pliska
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V
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001798:Blood Proteins / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000032:analysis*; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006400:Hematocrit; D006490:Hemostatics / Q000494:pharmacology*; D017483:Receptors, Vasopressin / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship; D014667:Vasopressins / Q000494:pharmacology*
D001798:Blood Proteins; D005343:Fibrinolytic Agents; D006490:Hemostatics; D017483:Receptors, Vasopressin; D014667:Vasopressins; D005169:Factor VIII