VASCULAR-RESPONSES TO VASOPRESSIN ANTAGONISTS IN MAN AND RAT

1. The effects of the non-peptide arginine vasopressin V-1 receptor antagonist (OPC-21268) and the nonpeptide V-2 receptor antagonist (OPC-31260) on vasopressin-induced contraction of human internal mammary arteries and rat mesenteric resistance arteries were investigated. 2. In human internal mammary arteries, the non-peptide V-1 receptor antagonist, OPC-21268, failed to antagonize vasopressin-induced contraction at low concentrations and potentiated the contraction at higher concentrations (300 nmol/l, P<0.05). A peptide selective V-1 receptor antagonist {[d(CH2)(5), sarcosine(7)]arginine vasopressin} potently inhibited the vasopressin-induced contraction, indicating the presence of functionally constrictor V-1 receptors in human internal mammary arteries. Both peptide (desGly-NH29[d(CH2)(5), D-Ile(2), Ile(4)]arginine vasopressin) and non-peptide 'selective' V-2 receptor antagonists (OPC-31260, 3 mu mol/l) significantly antagonized vasopressin-induced contraction (P<0.01), indicating partial V-1 receptor antagonist activity. 3. The vasopressin-induced contraction in human internal mammary arteries was reversed by high concentrations of the non-peptide V-2 receptor antagonist, OPC-31260, but not by the non-peptide V-1 receptor antagonist, OPC-21268. 4. The effects of OPC-21268 and OPC-31260 were specific to vascular vasopressin receptors as neither compound influenced endothelin- or noradrednaline-induced contraction in human internal mammary arteries. 5. In rat mesenteric resistance arteries, both OPC-21268 (10 nmol/l) and OPC-31260 (1 mu mol/l) antagonized vasopressin-induced contraction (P<0.01). 6. The results of this study in vitro indicate that in human internal mammary arteries, the non-peptide OPC-21268 is a partial V-1 receptor agonist with no V-1 receptor antagonist activity, whereas the nonpeptide OPC-31260 acts as a V-1 receptor antagonist. Both OPC-21268 and OPC-31260 have V-1 receptor antagonistic activity in vitro in the rat mesenteric resistance arteries. 7. These findings illustrate the complexity of the vasopressin receptor system and highlight the variability in results with peptide or non-peptide vasopressin analogues, between studies in vivo or in vitro, between species and across vascular beds.