Effects of vasopressin on the human non-pregnant uterus: studies with analogues of different vasopressor potencies.
The uterotonic effects of arginine8-vasopressin (AVP) have been studied on uterine strips from non-pregnant women. Concentration-dependent contractions could be recorded over a 10 min period in the presence of AVP (5.5.10(-10)-3.10(-7) M); the most reproducible recordings were obtained with tissue from the inner part of the myometrium. Analogues of AVP and oxytocin (OT), modified at positions 1 (2-hydroxy-3-mercaptopropionic acid, deamino-3-mercaptopropionic acid), 2 (Phe), 4 (Arg, Val), 7 (Sar) or 8 (Orn) were synthesized and tested for uterotonic activity on human and rat uterine strips, and for vasopressor and antidiuretic activity in the rat in vivo. There was a positive correlation between the activity of these analogues on non-pregnant human myometrial tissue with that in the rat vasopressor assay (r = 0.86, P less than 0.01) but none with their activity in the antidiuretic assay. For example, [Mpa1,D-Arg8]vasopressin had more than twice the antidiuretic activity of AVP but less than 0.2% of its pressor or human uterotonic potency (Mpa = 3-mercaptopropionic acid). Correspondingly, the specific pressor analogue [Hmp1,Phe2,Orn8]OT was as potent as AVP on the human uterus, but had less than 3% of its antidiuretic activity (Hmp = 2-hydroxy-3-mercaptopropionic acid). There was no correlation between the uterotonic activities of AVP or its analogues when non-pregnant human and rat tissues were compared, indicating that rat uterine tissue is a poor guide when testing analogues intended for clinical use in non-pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)
Melin
P
P
Research Department, Ferring Pharmaceuticals, Malmö, Sweden.
Trojnar
J
J
Carlsson
A M
AM
Bengtsson
B
B
Akerlund
M
M
Robinson
I
I
D000328:Adult; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects*
D010446:Peptide Fragments; D001127:Arginine Vasopressin; C045881:argipressin (4-9)