Binding and signal transduction characteristics of the nonpeptide vasopressin V1A receptor-selective antagonist YM218 in cultured rat mesangial cells

Vasopressin (AVP) causes mesangial cell contraction, proliferation and hypertrophy. The present study investigated the effects of YM218, a potent, nonpeptide AVP V-1A receptor-selective antagonist, on rat mesangial cells using binding, signal transduction and cell growth assays. Specific binding of H-3-AVP to rat mesangial cell plasma membranes was dependent upon time, temperature and membrane protein concentration. Scatchard plot analysis of equilibrium binding data revealed the existence of a single class of high-affinity binding sites with the expected V-1A receptor profile. YM218 showed high affinity for V-1A receptors, exhibiting a K-i value of 0.19 nmol/l. AVP concentration-dependently increased intracellular Ca2+ ([Ca2+](i)) levels, stimulated mitogen-activated protein (MAP) kinase and induced hyperplasia. Conversely, YM218 potently suppressed [Ca2+](i) elevation, activation of MAP kinase and hyperplasia induced by AVR These results indicate that YM218 displays both high affinity for rat mesangial cell V-1A receptors and high potency in inhibiting AVP-induced signal transduction and growth response. Therefore, YM218 is a useful pharmacologic tool for investigating the physiologic and pathophysiologic roles of AVP in kidney, and may have clinical application in the prevention or regression of mesangial cell growth. Copyright (c) 2006 S. Karger AG, Basel.