title: Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.
abstract: Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.
authors.affiliation: Department of Pharmacology and Molecular Biology, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Nagaizumi-cho, Sunto-gun, Shizuoka, Japan. masahiro.matsubara@kyowa.co.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsubara
authors.forename: Kozo
authors.initials: K
authors.lastname: Yao
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hasegawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D019610:Cytoprotection; D004095:Dihydropyridines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008244:Lysophosphatidylcholines / Q000037:antagonists & inhibitors / Q000633:toxicity; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008244:Lysophosphatidylcholines; D009569:Nitric Oxide; C061004:benidipine; D052250:Nitric Oxide Synthase Type III