HUMAN INTERNAL MAMMARY ARTERY RESPONSES TO NONPEPTIDE VASOPRESSIN ANTAGONISTS

1. OPC-21268 and OPC-31260 are newly developed orally active non-pepti de vasopressin (AVP) V-1 and V-2 receptor antagonists, respectively. T he effects of the two compounds on human vessels have not been studied . 2. The effects of the two compounds on AVP-induced contraction of hu man internal mammary arteries (IMA) were investigated. Their effects w ere compared with the peptide V-1 and V-2 antagonists d(CH2)(5)Sar(7)A VP (SAVP) and d(CH2)(5)D-Ileu(2)Ileu(4)AVP (Ileu(2)Ileu(4)AVP), respec tively. 3. The V-1 antagonist OPC-21268 failed to antagonize AVP-induc ed contraction at low concentrations and potentiated the contraction a t higher concentration (3 X 10(-7) mol/L, P<0.05). It also caused a mi ld direct contractile effect on IMA. In contrast, the peptide V-1 anta gonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V-1 receptors exist in IMA. Both the no npeptide and peptide V-2 antagonists OPC-31260 (3 X 10(-6) mol/L) and Ileu(2)Ileu(4)AVP significantly antagonized the AVP-induced contractio n (P<0.01). 4. The AVP-induced contraction was reversed by high concen trations of OPC-31260 (10(-6) mol/L-3 X 10(-5) mol/L) but not by OPC-2 1268 (up to 3 X 10(-6) mol/L). 5. These studies indicate that, in huma n IMA, OPC-21268 is a partial V-1 receptor agonist with no V-1 recepto r antagonist activity, while OPC-31260 is a V-1 receptor antagonist. T he results also indicate that Ileu(2)Ileu(4)AVP may be a V-1 receptor antagonist in humans.