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.
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
K M
KM
Jamil
T
T
Watanabe
A
A
Nakao
T
T
Okuda
K
K
Kurokawa
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017483:Receptors, Vasopressin / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C068644:OPC 21268; D003894:Deamino Arginine Vasopressin; D002118:Calcium