HUMAN INTERNAL MAMMARY ARTERY RESPONSES TO NONPEPTIDE VASOPRESSIN ANTAGONISTS

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V-1 and V-2 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 V-1 and V-2 antagonists d(CH2)(5)Sar(7)AVP (SAVP) and d(CH2)(5)D-Ileu(2)Ileu(4)AVP (Ileu(2)Ileu(4)AVP), respectively. 3. The V-1 antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 X 10(-7) mol/L, P<0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V-1 antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V-1 receptors exist in IMA. Both the nonpeptide and peptide V-2 antagonists OPC-31260 (3 X 10(-6) mol/L) and Ileu(2)Ileu(4)AVP 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 X 10(-5) mol/L) but not by OPC-21268 (up to 3 X 10(-6) mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial V-1 receptor agonist with no V-1 receptor antagonist activity, while OPC-31260 is a V-1 receptor antagonist. The results also indicate that Ileu(2)Ileu(4)AVP may be a V-1 receptor antagonist in humans.