title: Azelnidipine inhibits cultured rat aortic smooth muscle cell death induced by cyclic mechanical stretch.
abstract: Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c-Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect.
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kyotani
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nagayama
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Satoyasu
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Akira T
authors.initials: AT
authors.lastname: Komatsubara
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000873:Anthracenes; D000975:Antioxidants; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009861:Onium Compounds; D011725:Pyridines; C432165:pyrazolanthrone; D001383:Azetidinecarboxylic Acid; C007517:diphenyleneiodonium; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C061679:azelnidipine