In attempting to design an antagonist of the antidiuretic response to
arginine-vasopressin (AVP) [1-deaminopenicillamine,4-
valine,8-D-
arginine]vasopressin (
dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and
oxytocic activities.
dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-
valine,8-D-
arginine]vasopressin (
dVDAVP). Like
dVDAVP its
antidiuretic effect in conscious
diabetes insipidus rats is greatly prolonged when compared to AVP.
dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to
norepinephrine or
angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the
penicillamine substitution at position 1 in
dVDAVP increased its antivasopressor activity sixfold (
dVDAVP has a pA2 value of 7.03 +/- 0.11).
dPVDAVP is thus the most potent vasopressor antagonist yet reported.
dPVDAVP was also found to be a potent inhibitor of the in vitro
oxytocic response to
oxytocin (pA2 value = 7.23 +/- 0.04).
dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent
vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.