title: Effect of YM087, a potent nonpeptide vasopressin antagonist, on vasopressin-induced hyperplasia and hypertrophy of cultured vascular smooth-muscle cells.
abstract: We investigated the effects of YM087, a potent nonpeptide V1A and V2 vasopressin (AVP)-receptor antagonist, in binding and functional studies on rat vascular smooth-muscle cells (VSMCs). V1A AVP receptors on VSMCs were characterized by using the radioligand [3H]AVP. Specific binding of [3H]AVP was time dependent, reversible, and saturable. A single class of high-affinity binding sites with the expected V1A profile was identified. YM087 showed high affinity for V1A receptors with an inhibitory dissociation constant (Ki) value of 0.24 nM. In addition, YM087 potently and concentration-dependently inhibited AVP-induced increase in intracellular free calcium concentration and activation of mitogen-activated protein kinase. When added to growth-arrested VSMCs, AVP concentration-dependently induced hyperplasia and hypertrophy. YM087 prevented AVP-induced hyperplasia and hypertrophy of these cells in a concentration-dependent manner. YM087 had no agonistic activity in any biological assays used. These results suggest that YM087 displays high affinity for V1A receptors on VSMCs and high potency in inhibiting the AVP-induced physiological response. YM087 is a potent pharmacologic probe for investigating the physiologic and pathophysiologic roles of AVP in several diseases.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. Tsukuba, Ibaraki, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tahara
authors.forename: Y
authors.initials: Y
authors.lastname: Tomura
authors.forename: K
authors.initials: K
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Kusayama
authors.forename: J
authors.initials: J
authors.lastname: Tsukada
authors.forename: N
authors.initials: N
authors.lastname: Ishii
authors.forename: T
authors.initials: T
authors.lastname: Yatsu
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018929:Cell Culture Techniques; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D051381:Rats; D017483:Receptors, Vasopressin / Q000187:drug effects* / Q000378:metabolism; D014667:Vasopressins / Q000037:antagonists & inhibitors*
chemical_list: D001552:Benzazepines; D017483:Receptors, Vasopressin; C106389:conivaptan; D014667:Vasopressins; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium