title: OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling.
abstract: Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Internal Medicine, Asahi University, Mizuho, Japan; gt@dent.asahi-u.ac.jp.
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.affiliation: Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Company Limited, Tokushima, Japan;
authors.forename: Ayako
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Kenshi
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Company Limited, Tokushima, Japan;
authors.forename: Goro
authors.initials: G
authors.lastname: Miyakoda
authors.affiliation: Department of Food and Nutrition, Sonoda Women's University, Amagasaki, Japan; and.
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Company Limited, Tokushima, Japan;
authors.forename: Youichi
authors.initials: Y
authors.lastname: Yabuuchi
authors.affiliation: Department of Cardiovascular Medicine, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan;
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015996:Survival Rate; D014665:Vasodilator Agents / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D000814:Aniline Compounds; D019394:Ki-67 Antigen; D010880:Piperidines; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C400276:OPC 28326
keywords: angiogenesis; late reperfusion; myocardial infarction; remodeling