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.