The vasorelaxing action of labedipinedilol-A involves endothelial cell-derived NO and eNOS expression caused by calcium influx.
Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-NG-nitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS- and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2'-azobis (2-amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endothelium-dependent vasorelaxation by labedipinedilol-A is mediated through Ca2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.
Liou
Shu-Fen
SF
Department and Graduate Institute of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan.
Wu
Jiunn-Ren
JR
Lai
Wen-Ter
WT
Sheu
Sheng-Hsiung
SH
Chen
Ing-Jun
IJ
Yeh
Jwu-Lai
JL
D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D019332:Endothelin-1 / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar
D000840:Anisoles; D000975:Antioxidants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D019332:Endothelin-1; D005609:Free Radicals; C500368:labedipinedilol A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006162:Guanylate Cyclase; D005978:Glutathione; D006152:Cyclic GMP