HUMAN INTERNAL MAMMARY ARTERY RESPONSES TO NON-PEPTIDE VASOPRESSIN ANTAGONISTS

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V₁ and V₂ receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V₁ and V₂ antagonists d(CH₂)_sSar⁷AVP (SAVP) and d(CH₂)₅D-Ileu²11eu⁴AVP (Ileu² Ileu⁴AVP), respectively. 3. The V₁ antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 × 10^?-⁷ mol/L, P<0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V₁ antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V₁ receptors exist in IMA. Both the nonpeptide and peptide V₂ antagonists OPC-31260 (3X10^?-⁶ mol/L) and Ileu²Ileu⁴AVP significantly antagonized the AVP-induced contraction (P<0.01). 4. The AVP-induced contraction was reversed by high concentrations of OPC-31260 (10^?-⁶ mol/L-3×10^?-⁵ mol/L) but not by OPC-21268 (up to 3X 10^?-⁵ mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial VI receptor agonist with no V₁ receptor antagonist activity, while OPC-31260 is a V1 receptor antagonist. The results also indicate that Ileu² Ileu⁴AVP may be a V_l receptor antagonist in humans.