Author: Junko Tsukada ; Wataru Uchida ; Atsuo Tahara ; Takeyuki Yatsu ; Nobuaki Taniguchi ; Noe Ishii ; Koh-ichi Wada ; Yuichi Tomura ; Toshiyuki Kusayama ; Akihiro Tanaka

The antagonistic properties of YM471, a potent nonpeptide vasopressin (AVP) V(1A) and V(2) receptor antagonist, were characterized using human coronary artery smooth muscle cells (CASMC). YM471 potently inhibited specific binding of 3H-AVP to V(1A) receptors on human CASMC, exhibiting a K(i) value of 0.49 nM. Furthermore, YM471 inhibited the AVP-induced increase in intracellular free Ca(2+) concentration with an IC(50) value of 1.42 nM, but exerted no agonistic activity on CASMC. Additionally, while AVP concentration-dependently induced hyperplasia and hypertrophy in CASMC, YM471 prevented these AVP-induced growth effects, exhibiting IC(50) values of 0.93 and 2.64 nM, respectively. These results indicate that YM471 has high affinity for V(1A) receptors on, and high potency in inhibiting AVP-induced physiologic responses of, human CASMC.

01 Sep 2002·Journal of HypertensionQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Taniguchi, Nobuaki ; Tsukada, Junko ; Ishii, Noe ; Tahara, Atsuo ; Uchida, Wataru ; Yatsu, Takeyuki ; Tanaka, Akihiro ; Kusayama, Toshiyuki ; Wada, Koh-ichi ; Tomura, Yuichi

OBJECTIVETo 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).METHODSBinding 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.RESULTSYM471 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.CONCLUSIONSThese results indicate that YM471 has high affinity for V receptors on, and potently inhibits AVP-induced physiologic responses of, human VSMCs.

01 Jun 2002·European Journal of PharmacologyQ3 · MEDICINE

Pharmacological characterization of YM471, a novel potent vasopressin V1A and V2 receptor antagonist

Q3 · MEDICINE

Article

Author: Ishii, Noe ; Yatsu, Takeyuki ; Kusayama, Toshiyuki ; Wada, Koh-ichi ; Tsukada, Junko ; Aoki, Motonori ; Tahara, Atsuo ; Taniguchi, Nobuaki ; Tomura, Yuichi ; Uchida, Wataru ; Tanaka, Akihiro

The pharmacologic profile of YM471 ((Z)-4'-[4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]-2-phenylbenzanilide monohydrochloride), a novel potent vasopressin V(1A) and V(2) receptor antagonist, was investigated using several in vitro and in vivo techniques. YM471 showed high affinity for rat vasopressin V(1A) and V(2) receptors, exhibiting K(i) values of 0.16 and 0.77 nM, respectively. In contrast, YM471 exhibited much lower affinity for rat vasopressin V(1B) and oxytocin receptors, with K(i) values of 10.5 microM and 31.0 nM, respectively. In conscious rats, oral administration of YM471 (0.1-3.0 mg/kg) produced dose-dependent inhibition of the pressor response caused by exogenous vasopressin and increased urine excretion and decreased urine osmolality; this effect lasted more than 8 h. In all biological assays used, YM471 exhibited no agonistic activity. These results demonstrate that YM471 exerts potent and long-lasting antagonistic activity on both vasopressin V(1A) and V(2) receptors, and that this compound may be a useful tool for clarifying the physiologic and pathophysiologic roles of vasopressin and the therapeutic usefulness of the vasopressin receptor antagonist.

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