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

Abstract

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 (3)H-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 Ca(2+) ([Ca(2+)](i)) levels, stimulated mitogen-activated protein (MAP) kinase and induced hyperplasia. Conversely, YM218 potently suppressed [Ca(2+)](i) elevation, activation of MAP kinase and hyperplasia induced by AVP. 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.

• Authors: Atsuo Tahara, Junko Tsukada, Yuichi Tomura, Toshiyuki Kusayama, Kazuhiro Momose, Nobuaki Taniguchi, Takeshi Suzuki, Takeyuki Yatsu, Masayuki Shibasaki
• Journal: Pharmacology (Pharmacology) Vol. 78 Issue 2 Pg. 81-90 ( 2006) ISSN: 0031-7012 [Print] Switzerland
• PMID: 16966841 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2006 S. Karger AG, Basel.

Chemical References

• 4'-(4,4-difluoro-5-(2-oxo-2-(4-piperidinopiperidino)ethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-methyl-3-furanilide
• Antidiuretic Hormone Receptor Antagonists
• Benzazepines
• Piperidines
• Receptors, Vasopressin
• Mitogen-Activated Protein Kinase Kinases
• Calcium

Topics

• Animals
• Antidiuretic Hormone Receptor Antagonists
• Benzazepines (pharmacology)
• Binding, Competitive
• Calcium (metabolism)
• Cell Membrane (drug effects, enzymology, metabolism)
• Cells, Cultured
• Male
• Mesangial Cells (drug effects, enzymology, metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Piperidines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Vasopressin (agonists)
• Signal Transduction (drug effects)