title: Betulinic acid ameliorates endothelium-dependent relaxation in L-NAME-induced hypertensive rats by reducing oxidative stress.
abstract: Zizyphi Spinosi semen (ZSS) is one of the most widely used traditional Chinese herbs with protective effects on the cardiovascular system. It is not clear whether betulinic acid (BA), the key active constituent of ZSS, has beneficial cardiovascular effects on N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. The objective of this study was to investigate the effect of BA on endothelium-dependent vasorelaxation in isolated aortic rings from L-NAME-induced hypertensive rats and its underlying mechanisms. Male Sprague-Dawley rats were injected with L-NAME (15 mg/kg/d, i.p.) for 4 weeks to induce hypertension. After treatment with L-NAME for 2 weeks, rats with mean blood pressure >120 mm Hg measured by tail-cuff method were considered hypertensive and then injected with BA (0.8, 4, 20 mg/kg/d, i.p.) for the last 2 weeks. The effect of BA on the tension of rat thoracic aortic rings was measured in an organ bath system. The levels of nitric oxide (NO), reactive oxygen species (ROS), and the activity of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in aortas were assayed. We found that BA (0.1-100 μM) evoked a concentration-dependent vasorelaxation in endothelium-intact normal rat aortic rings, which was significantly attenuated by pretreatment with L-NAME (100 μM) or methylene blue (MB, 10 μM), but not by indomethacin (10 μM). Pretreatment with EC(50) (1.67 μM) concentration of BA enhanced the acetylcholine (ACh)-induced vasorelaxation, which was also markedly reversed by both L-NAME and MB. The blood pressure in hypertensive rats increased to 135.22±5.38 mm Hg (P<0.01 vs. control group), which was markedly attenuated by high dose of BA. The ACh-induced vasorelaxation in hypertensive rat aortic rings was impaired, which was markedly improved by chronic treatment with BA (20 mg/kg/d) for 2 weeks. The increase of ROS level and the decrease of NO level, SOD and eNOS activities in hypertensive rat aortas were all markedly inhibited by BA. These results indicate that BA decreased blood pressure and improved ACh-induced endothelium-dependent vasorelaxation in L-NAME-induced hypertension rats, which may be mediated by reducing oxidative stress and retaining the bioavailability of NO in the cardiovascular system.
authors: Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors: Jia-Yin
authors: JY
authors: Fu
authors: Ling-Bo
authors: LB
authors: Qian
authors: Lie-Gang
authors: LG
authors: Zhu
authors: Hao-Te
authors: HT
authors: Liang
authors: Yi-Nuo
authors: YN
authors: Tan
authors: Han-Ti
authors: HT
authors: Lu
authors: Jian-Feng
authors: JF
authors: Lu
authors: Hui-Ping
authors: HP
authors: Wang
authors: Qiang
authors: Q
authors: Xia
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D053978:Pentacyclic Triterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects*; D000094062:Betulinic Acid
chemical_list: D000959:Antihypertensive Agents; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester; D000094062:Betulinic Acid