Natriuretic action of neurohypophysial peptides: Effects of agonists and antagonists and implication of natriuretic receptor

Neurohypophysial peptides possess natriuretic activity. Although it has been shown that the natriuretic action of these peptides can be dissociated from their antidiuretic activity (a V₂-receptor mediated response), it is not known whether the V₁-receptor or yet a third receptor type mediates the natriuretic response. Also, it has not been studied what effects V₁- and V₂-antagonists may have on urinary sodium excretion. To define this, we have studied the effects of four oxytocin (OT) agonists: arginine-vasopressin, OT, [Leu⁴)OT and [cyclo-Leu⁸]OT; two V₁-receptor antagonists: [penicillamine¹,Phe(Methyl)²,Thr⁴,Orn⁸)OT and [penicillamine¹,D-Phe)Ethyl)²,Thr⁴,Orn⁸]OT and one V₂-receptor antagonist: d-(CH₂)₅[D-Ile²,α-aminobutyric acid⁴]arginine-vasopressin on renal excretion of water and electrolytes in anesthetized rats under water diuresis. We also studied the effects of the antagonists on the OT-induced antidiuretic and natriuretic responses. Only the agonists, but not the antagonists, were found to have natriuretic activity. The natriuretic potency, was not related to the peptide's antidiuretic activity, but was in the same rank order as their oxytocic activity (a V₁-agonist effect). The effects of the antagonists on the OT-induced renal responses were studied at two dose levels, representing a strong and near maximal of their respective V₁ and V₂ inhibitory doses. The V₁-antagonist had no effect on the antidiuretic response to OT but inhibited the natriuretic response in a dose-dependent manner. The antinatriuretic effect was also long-lasting as its antioxytocic activity. The V₂-antagonist inhibited the antidiuretic response to OT in a dose-dependent manner but only the high dose inhibited the natriuretic response. These results indicate that the natriuretic action of OT was not mediated by V₂-receptors and antinatriuresis was not specific for V₁-antagonist. This suggests that a V₁-subtype or a third receptor type may be involved.