Abstract | OBJECTIVE: 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.
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Authors | Atsuo Tahara, Junko Tsukada, Yuichi Tomura, Toshiyuki Kusayama, Koh-Ichi Wada, Noe Ishii, Takeyuki Yatsu, Wataru Uchida, Nobuaki Taniguchi, Akihiro Tanaka |
Journal | Journal of hypertension
(J Hypertens)
Vol. 20
Issue 9
Pg. 1807-14
(Sep 2002)
ISSN: 0263-6352 [Print] England |
PMID | 12195123
(Publication Type: Journal Article)
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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
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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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