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Effect of YM471, an orally active non-peptide arginine vasopressin receptor antagonist, on human vascular smooth muscle cells.

AbstractOBJECTIVE:
To investigate the effects of YM471, a non-peptide arginine vasopressin (AVP) V1A and V2 receptor antagonist, on the AVP-induced growth responses in human vascular smooth muscle cells (VSMCs).
METHODS:
Binding of YM471 to V1A receptors on VSMCs was measured using [3H]AVP. Intracellular free Ca2+ concentration was measured by fura 2 fluorescence. Mitogen-activated protein (MAP) kinase activity was determined using the p42/p44 MAP kinase specific peptide and [gamma- 32P]ATP as substrates. The effect of AVP on hyperplasia and hypertrophy of VSMCs was determined by cell number and protein content measurements.
RESULTS:
YM471 potently and concentration-dependently inhibited the specific binding of [ 3H]AVP to V1A receptors on VSMCs, exhibiting an inhibition constant (Ki ) of 0.35 nmol/l. YM471 inhibited the AVP-induced increase in intracellular free Ca concentration with an 50% inhibition concentration (IC50 ) of 2.01 nmol/l and inhibited the activation of MAP kinase with an IC50 of 6.11 nmol/l. In addition, AVP concentration-dependently induced hyperplasia and hypertrophy in VSMCs, but YM471 prevented these AVP-induced growth effects, exhibiting IC50 values of 2.31 and 0.23 nmol/l, respectively.
CONCLUSIONS:
These results indicate that YM471 has high affinity for V receptors on, and potently inhibits AVP-induced physiologic responses of, human VSMCs.
AuthorsAtsuo Tahara, Junko Tsukada, Yuichi Tomura, Toshiyuki Kusayama, Koh-Ichi Wada, Noe Ishii, Takeyuki Yatsu, Wataru Uchida, Nobuaki Taniguchi, Akihiro Tanaka
JournalJournal of hypertension (J Hypertens) Vol. 20 Issue 9 Pg. 1807-14 (Sep 2002) ISSN: 0263-6352 [Print] England
PMID12195123 (Publication Type: Journal Article)
Chemical References
  • 4'-(4,4-difluoro-5-(2-(4-dimethylaminopiperidino)-2-oxoethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-phenylbenzanilide
  • Antidiuretic Hormone Receptor Antagonists
  • Azepines
  • Piperidines
  • Receptors, Vasopressin
  • Arginine Vasopressin
  • Mitogen-Activated Protein Kinases
Topics
  • Antidiuretic Hormone Receptor Antagonists
  • Aorta (metabolism, pathology)
  • Arginine Vasopressin (pharmacology)
  • Azepines (pharmacology)
  • Cells, Cultured
  • Enzyme Activation (drug effects)
  • Humans
  • Hyperplasia
  • Hypertrophy
  • Mitogen-Activated Protein Kinases (metabolism)
  • Muscle, Smooth, Vascular (metabolism, pathology)
  • Piperidines (pharmacology)
  • Receptors, Vasopressin (metabolism)

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