DISTINCT MECHANISMS OF ACTION OF V1 ANTAGONISTS OPC-21268 AND [D(CH2)5TYR(ME)AVP] IN MESANGIAL CELLS

The effects of two arginine vasopressin (AVP) V1 receptor antagonists, a peptide analogue [d(CH2)5Tyr(Me)AVP] and an orally active non-peptide OPC- 21268, on AVP-stimulated Ca transients and 3H-AVP binding were examined in cultured rat mesangial cells. Although both [d(CH2)5Tyr(Me)AVP] and OPC- 21268 dose-dependently inhibited AVP-stimulated Ca transients and 3H-AVP binding, their effects were quite different. Magnitude of inhibition of Ca transients by OPC-21268 was comparable when OPC-21268 was added together with or 5 min prior to AVP. However, the inhibition by [d(CH2)5Tyr(Me)AVP] was greater when it was added prior to AVP than when it was added together with AVP. Moreover, washing mesangial cells after OPC-21268 treatment, but not after [d(CH2)5Tyr(Me)AVP] treatment, completely restored AVP-stimulated Ca transients to the control level without antagonists. These results indicate that the cellular mechanisms for two V1 receptor antagonists are different: while the effect of OPC-21268 as a vasopressin antagonist appears to be competitive and reversible, the effect of the peptide antagonist [d(CH2)5Tyr(Me)AVP] seems to be rather irreversible in nature. © 1993 Academic Press, Inc.