复方比索洛尔硝酸异山梨酯透皮贴剂自发性高血压大鼠的心血管保护作用

复方比索洛尔硝酸异山梨酯透皮贴剂自发性高血压大鼠的心血管保护作用

魏巍, 傅继华^*, 苏长海, 单英, 王渊, 孔树佳, 赵继会, 吕万良^*^*, 王树明, 王丽

1. 中国药科大学药学院, 江苏南京 210009;
2. 北京大学药学院; 天然药物及仿生药物国家重点实验室, 北京 100191;
3. 北京康倍得制药有限公司, 北京 100029

收稿日期:2008-04-12 修回日期:2008-08-10 出版日期:2008-09-15 发布日期:2008-09-15
通讯作者: 傅继华*

A continued study on the bisoprolol and isosorbide dinitrate transdermal patches: cardiovascular protection in spontaneously hypertensive rats

Wei Wei, Ji-Hua Fu^*, Chang-Hai Su , Ying Shan, Yuan Wang, Shu-Jia Kong, Ji-Hui Zhao, Wan-Liang Lu^*^*, Shu-Ming Wang, Li Wang

1. Department of Physiology, China Pharmaceutical University, Nangjing 210009, China;
2. The State Key Laboratory of Natural and Biomimetic Drugs; School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;
3. Beijing Kangbeide Pharmaceutical Co. Ltd, Beijing 100029, China

Received:2008-04-12 Revised:2008-08-10 Online:2008-09-15 Published:2008-09-15
Contact: Ji-Hua Fu*

摘要/Abstract

摘要：

探讨复方比索洛尔硝酸异山梨酯透皮贴剂对自发性高血压大鼠的心血管保护作用的优势。自发性高血压大鼠随机分为空白贴组、比索洛尔口服组 (BP-FT, 20.0 mg/kg)、比索洛尔贴剂组(BP-TP, 20.0 mg/kg)、硝酸异山梨酯贴剂组(ISDN-TP, 20.0 mg/kg)、联合给药组(BP, 8 mg/kg; ISDN, 12 mg/kg)。观察42天治疗期内复方比索洛尔硝酸异山梨酯透皮贴剂对其血压的影响, 测定与心血管保护有关的生化指标, 并对心肌和血管结构进行了评定。BP和ISDN具有协同的抗压作用。联合给药对与单独给BP相比, 有着相同的降低心率的作用, 并且在控制血压波动方面有明显的优势。而ISDN的单独给药没有明显的抗压或降心率的作用。联合给药组能显著增加大鼠血液中心房钠肽和一氧化碳的含量, 减少心肌组织中羟脯氨酸和内皮素-1的含量, 降低血液中内皮素-1和丙二醛的浓度。同时, 联合用药组还可以减轻心肌肥大, 减小血管腔壁比, 显著增强Ach诱导的内皮依赖性舒张反应。复方比索洛尔硝酸异山梨酯透皮贴剂长期给药不仅可明显降低血压, 产生平稳的降压效果, 且对心脏和血管产生明显的保护作用, 这种协同作用可能在心血管保护的长期治疗中发挥优势。

关键词: 透皮贴剂, 透皮贴剂, 透皮贴剂, 高血压, 高血压, 高血压, 硝酸异山梨酯, 硝酸异山梨酯, 硝酸异山梨酯, 比索洛尔, 比索洛尔, 比索洛尔, 心血管保护, 心血管保护, 心血管保护

Abstract:

The objective of the present study is to examine cardiovascular protective action of a newly developed transdermal patch by incorporating bisoprolol and isosorbide dinitrate in spontaneously hypertensive rats. As the combination therapy with these two synergistic drugs at low doses through a suitable form of administration could provide optimal therapeutic benefit, we further evaluated the effects of a 42 d period of anti-hypertensive treatment in spontaneously hypertensive rats. Rats were divided into the following five groups: control (blank patch), bisoprolol fumarate tablets (BP-FT, 20.0 mg/kg, i.g.), bisoprolol transdermal patch (BP-TP, 20.0 mg/kg), isosorbide dinitrate transdermal patch (ISDN-TP, 20.0 mg/kg), and the combination of BP and ISDN in a transdermal patch at low doses (8 and 12 mg/kg, respectively). The effects of treatment were evaluated via biochemical indicators related to cardiovascular protection, structure and function. The combination therapy had synergistic anti-hypertensive effects and significantly reduced blood pressure with the benefit of controlling blood pressure variability compared to BP-FT and BP-TP. The combined treatment also reduced heart rate as well as BP-FT and BP-TP, while ISDN-TP had no evident effects on blood pressure, heart rate, and cardiovascular protection. Combination therapy was superior to BP-TP and BP-FT at increasing blood atrial natriuretic peptide and nitric oxide, while also reducing cardiac hydroxyproline and endothelin-1 with no difference in blood endothelin-1 and cardiac malondialdehyde levels. Cardiovascular remodeling differed among the groups, with the combination therapy reducing cardiac hypertrophy and the aortic media/lumen ratio. The consequential improvements in relaxation in response to cumulative concentrations of acetylcholine may explain the associated improvement in endothelial function. Combination treatment with a transdermal patch exhibited a synergistic therapeutic effect. Such favorable cardiovascular effects with nitric oxide donors and β-blockade combination through a transdermal patch may provide long-term cardiovascular protection during anti-hypertensive treatment.

Key words: Transdermal patch, Transdermal patch, Hypertension, Hypertension, Isosorbide dinitrate, Isosorbide dinitrate, Bisoprolol, Bisoprolol, Cardiovascular protection, Cardiovascular protection

Supporting: Foundation item: ‘863’ High Technology R&D Project of Ministry of Science and Technology of China (Grant No. 2004AA2Z3073).
*Corresponding author. Tel.: 86-25-85339624; fax: 86-25-86634069;

魏巍, 傅继华^*, 苏长海, 单英, 王渊, 孔树佳, 赵继会, 吕万良^*^*, 王树明, 王丽
. 复方比索洛尔硝酸异山梨酯透皮贴剂自发性高血压大鼠的心血管保护作用[J]. .

Wei Wei, Ji-Hua Fu^*, Chang-Hai Su , Ying Shan, Yuan Wang, Shu-Jia Kong, Ji-Hui Zhao, Wan-Liang Lu^*^*, Shu-Ming Wang, Li Wang. A continued study on the bisoprolol and isosorbide dinitrate transdermal patches: cardiovascular protection in spontaneously hypertensive rats
[J]. .

参考文献

[1] Haneda, T.; Ido, A.; Fujikane, T.; Tanaka, H.; Tanazawa, S.; Morimoto, H.; Kato, J.; Kanaya, K.; Honda, H.; Sakai, H.; Akita, N.; Hirayama, T.; Onodera, S.; Kikuchi, K. NipponRonen Igakkai Zasshi. 1998, 35, 33-38.
[2] Haeusler, G.; Schliep, H.J.; Schelling, P.; Becker, K.H.; Klockow, M.; Minck, K.O.; Enenkel, H.J.; Schulze, E.; Bergmann, R.; Schmitges, C. J. Cardiovasc. Pharmacol. 1986, 8, S2-15.
[3] Leopold, G. J. Cardiovasc. Pharmacol. 1986, 8, S16-20. Ohta, M.; Nanri, H.; Matsushima, Y.; Sato, Y.; Ikeda, M.
[4] Ohta, M.; Nanri, H.; Matsushima, Y.; Sato, Y.; Ikeda, M. Hypertens. Res. 2005, 28, 779-786.
[5] Taylor, T.; Chasseaud, L.F.; Major, R.M.; Leaf, F.C.; Bonn, R.; Darragh, A.; Lambe, R.F. Biopharm. Drug Dispos. 1985, 6, 119-129.
[6] Johnson, K.I.; Gladigau, V.; Schnelle, K. Arzneimittelforsch. 1981, 31, 1026-1029.
[7] Modamio, P.; Lastra, C.F.; Marino, E.L. Int. J. Pharm. 2000, 194, 249-259.
[8] Bosch, J.; Garcia-Pagan, J.C.; Feu, F.; Luca, A.; Fernandez, M.; Pizcueta, P.; Rodes, J. Hepatology. 1993, 17, S41-45.
[9] Zhao, J.H.; Fu, J.H.; Wang, S.M.; Su, C.H.; Shan, Y.; Kong, S.J.; Wang, Y.; Lu, W.L.; Zhang, H.; Zhang, S.; Li, L.; Zhang, E.H.; Wang, L.; Pei, Q.L.; Wang, J.C.; Zhang, X.; Zhang, Q. Int. J. Pharm. 2007, 337, 88-101.
[10] Mougenot, N.; Lesnik, P.; Ramirez-Gil, J.F.; Nataf, P.; Diczfalusy, U.; Chapman, M.J.; Lechat, P. Atherosclerosis. 1997, 133, 183-192.
[11] Costa, V.A.; Vianna, L.M.; Aguila, M.B.; Mandarim-de-Lacerda, C.A. J. Nutr. Biochem. 2005, 16, 251-256.
[12] Mougenot, N.; Mediani, O.; Lechat, P. Pharm. Res. 2005, 51, 359-365.
[13] Parati, G.; Mancia, G. Blood Press. Monit. 2001, 6, 341-347.
[14] Liu, J.G.; Xu, L.P.; Chu, Z.X; Miao, C.Y.; Su, D.F. J. Hypertens. 2003, 21, 1961-1967.
[15] Xie, H.H.; Shen, F.M.; Zhang, X.F.; Jiang, Y.Y.; Su, D.F. Eur. J. Pharm. 2006, 543, 77-82.
[16] Moncada, S.; Palmer, R.M.; Higgs, E.A. Pharm. Rev. 1991, 43, 109-142.
[17] Furchgott, R.F.; Vanhoutte, P.M. FASEB J. 1989, 3, 2007-2018.
[18] Vane, J.R.; Anggard, E.E.; Botting, R.M. N. Engl. J. Med. 1990, 323, 27-36.
[19] Dzau, V.J. J. Cardiovasc. Pharmacol. 1987, 10, S9-16.
[20] Balati, B.; Phung, H.; Pousset, F.; Isnard, R.; Boisvieux, A.; Carayon, A.; Komajda, M.; Lechat, P. Fundam Clin. Pharmacol. 2002, 16, 361-368.
[21] Benetos, A.; Poitevin, P.; Prost, P.L.; Safar, M.E.; Levy, B.I. Am. J. Hypertens. 1994, 7, 186-192.
[22] Brilla, C.G.; Funck, R.C.; Rupp, H. Circulation. 2000, 102, 1388-1393.
[23] Chua, B.H.; Krebs, C.J.; Chua, C.C.; Diglio, C.A. Am. J. Physiol. 1992, 262, E412-416.
[24] Hofman, F.M.; Chen, P.; Jeyaseelan, R. Blood. 1998, 92, 3064-3072.
[25] Davie, N.; Haleen, S.J.; Upton, P.D.; Polak, J.M.; Yacoub, M.H.; Morrell, N.W.; Wharton, J. Am. J. Respir. Crit. Care Med. 2002, 16, 398-405.
[26] Pedram, A.; Razandi, M.; Hu, R.M.; Levin, E.R. J. Biol. Chem. 1997, 272, 17097-17103.
[27] Ruef, J.; Moser, M.; Kubler, W.; Bode, C. Cardiovasc. Pathol. 2001, 10, 311-315.
[28] Kung, C.F.; Luscher, T.F. Hypertension. 1995, 25, 194-200.
[29] Linder, A.E.; McCluskey, L.P.; Cole, K.R.; Lanning, K.M.; Webb, R.C. Pharm. Exp. Ther. 2005, 314, 9-15.
[30] Hasegawa, T.; Takagi, S.; Nishimaki, K.; Morita, K.; Nakajima, S. Biochem. Int. 1992, 26, 653-658.
[31] Esper, R.J.; Nordaby, R.A.; Vilarino, J.O.; Paragano, A.; Cacharron, J.L.; Machado, R.A. Cardiovasc. Diabetol. 2006, 5, 4.