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Planta Med 2009; 75(14): 1476-1481
DOI: 10.1055/s-0029-1185774
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Demethylbellidifolin Prevents Nitroglycerin Tolerance via Improved Aldehyde Dehydrogenase 2 Activity

Rui-Zheng Shi1 , Xiao-Hui Li2 , Su-Jie Jia2 , Qiong-Mei Fu1 , Yue-Rong Chen2 , Jia Chen3 , An Chen1 , Shi-Xun Li1 , Gui-San Tan2 , Yuan-Jian Li2 , Guo-Gang Zhang1
  • 1Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China
  • 2Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, P. R. China
  • 3Department of Nursing, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
Further Information

Publication History

received Dec. 11, 2008 revised April 27, 2009

accepted April 29, 2009

Publication Date:
16 June 2009 (online)

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Abstract

The aim of this study was to investigate the effect of demethylbellidifolin (DMB), a major xanthone compound of Swertia davidi Franch, on nitroglycerin (NTG) tolerance. In the in vivo portion of the study, pretreatment of Sprague-Dawley rats with NTG (10 mg/kg) for 8 days caused tolerance to the depressor effect of NTG. This was evident because the depressor effect of NTG (150 µg/kg, i. v.) was almost completely abolished in the tolerant rats. The tolerance could be diminished by treatment with DMB. In the in vitro study, the exposure of aortic rings of Sprague-Dawley rats to NTG (10 µM) for 30 min caused tolerance to the vasodilating effect of NTG. The tolerance is evident because of a substantial right shift of the NTG concentration-relaxation curves. This shift was reduced by pretreatment of the aortic rings with DMB. In cultured human umbilical vein endothelial cells (HUVECs), incubation of NTG for 16 h increased reactive oxygen species (ROS) production, attenuated cyclic guanosine monophosphate (cGMP) levels and decreased the activity of aldehyde dehydrogenase 2 (ALDH-2), the main enzyme responsible for NTG bioactivation. All the effects mentioned above were prevented by co-incubation with DMB. In conclusion, DMB prevents NTG tolerance via increasing ALDH-2 activity through decreasing ROS production.

Key words

demethylbellidifolin - nitroglycerin tolerance - reactive oxygen species - aldehyde dehydrogenase 2

References

  • 1 Katsuki S, Arnold W P, Murad F. Effects of sodium nitroprusside, nitroglycerin, and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues.  J Cyclic Nucleotide Res. 1977;  3 239-247
    PubMedSearch in Google Scholar
  • 2 Munzel T, Sayegh H, Freeman B A, Tarpey M M, Harrison D G. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.  J Clin Invest. 1995;  95 187-194
    CrossrefPubMedSearch in Google Scholar
  • 3 Dikalov S, Fink B, Skatchkov M, Sommer O, Bassenge E. Formation of reactive oxygen species in various vascular cells during glyceryltrinitrate metabolism.  J Cardiovasc Pharmacol Ther. 1998;  3 51-62
    CrossrefPubMedSearch in Google Scholar
  • 4 Sage P R, de la Lande I S, Stafford I, Bennett C L, Phillipov G, Stubberfield J, Horowitz J D. Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion.  Circulation. 2000;  102 2810-2815
    PubMedSearch in Google Scholar
  • 5 Otto A, Fontaine D, Fontaine J, Berkenboom G. Rosuvastatin treatment protects against nitrate-induced oxidative stress.  J Cardiovasc Pharmacol. 2005;  46 177-184
    CrossrefPubMedSearch in Google Scholar
  • 6 Fontaine D, Otto A, Fontaine J, Berkenboom G. Prevention of nitrate tolerance by long-term treatment with statins.  Cardiovasc Drugs Ther. 2003;  17 123-128
    CrossrefPubMedSearch in Google Scholar
  • 7 Chen Z, Zhang J, Stamler J S. Identification of the enzymatic mechanism of nitroglycerin bioactivation.  Proc Natl Acad Sci USA. 2002;  99 8306-8311
    CrossrefPubMedSearch in Google Scholar
  • 8 Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mülsch A, Schulz E, Keaney Jr J F, Stamler J S, Münzel T. Central role of mitochondrial aldehyde dehydrogenase 2 and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.  J Clin Invest. 2004;  113 482-489
    PubMedSearch in Google Scholar
  • 9 Mackenzie I S, Maki-Petaja K M, McEniery C M, Bao Y P, Wallace S M, Cheriyan J, Monteith S, Brown M J, Wilkinson I B. Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans.  Arterioscler Thromb Vasc Biol. 2005;  25 1891-1895
    CrossrefPubMedSearch in Google Scholar
  • 10 Esplugues J V, Rocha M, Nunez C, Bosca I, Ibiza S, Herance J R, Ortega A, Serrador J M, D'Ocn P, Victor V M. Complex I dysfunction and tolerance to nitroglycerin: an approach based on mitochondrial-targeted antioxidants.  Circ Res. 2006;  99 1067-1075
    CrossrefPubMedSearch in Google Scholar
  • 11 Daiber A, Oelze M, Coldewey M, Bachschmid M, Wenzel P, Sydow K, Wendt M, Kleschyov A L, Stalleicken D, Ullrich V, Mulsh A, Munzel T. Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.  Mol Pharmacol. 2004;  66 1372-1382
    CrossrefPubMedSearch in Google Scholar
  • 12 Jiang D J, Dai Z, Li Y J. Pharmacological effects of xanthones as cardiovascular protective agents.  Cardiovasc Drug Rev. 2004;  22 91-102
    CrossrefPubMedSearch in Google Scholar
  • 13 Jiang D J, Tan G S, Zhou Z H, Xu K P, Ye F, Li Y J. Protective effects of demethylbellidifolin on myocardial ischemia-reperfusion injury in rats.  Planta Med. 2002;  68 710-713
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Jiang D J, Jiang J L, Tan G S, Huang Z Z, Deng H W, Li Y J. Demethylbellidifolin inhibits adhesion of monocytes to endothelial cells via reduction of tumor necrosis factor alpha and endogenous nitric oxide synthase inhibitor level.  Planta Med. 2003;  69 1150-1152
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Jiang D J, Jiang J L, Zhu H Q, Tan G S, Liu S Q, Xu K P. Demethylbellidifolin preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level.  J Ethnopharmacol. 2004;  93 295-306
    CrossrefPubMedSearch in Google Scholar
  • 16 Tan G S, Xu P S, Tian H Y, Xu K P, Dai Z Y. Studies on the chemical constituents of Swertia davidi.  Chin Pharm J. 2000;  35 441-443
    PubMedSearch in Google Scholar
  • 17 Chen Y R, Lie S D, Wang S, Jiang D J, Shi R Z, Zhou Z, Guo R, Zhang Z, Li Y G. Reduction of endogenous CGRP release in nitroglycerin tolerance: role of ALDH‐2.  Eur J Pharmacol. 2007;  571 44-50
    CrossrefPubMedSearch in Google Scholar
  • 18 Zhou Z H, Deng H W, Li Y J. The depressor effect of nitroglycerin is mediated by calcitonin gene-related peptide.  Life Sci. 2001;  69 1313-1320
    CrossrefPubMedSearch in Google Scholar
  • 19 Zhang G G, Shi R Z, Jiang D J, Chen Y R, Jia C, Tang Z Y, Bai Y P, Xiao H B, Li Y J. Involvement of the endothelial DDAH/ADMA pathway in nitroglycerin tolerance: the role of ALDH‐2.  Life Sci. 2008;  82 699-707
    CrossrefPubMedSearch in Google Scholar
  • 20 Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance.  Circ Res. 2005;  30 618-628
    PubMedSearch in Google Scholar
  • 21 Zhang J, Chen Z, Cobb F R, Stamler J S. Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model.  Circulation. 2004;  110 750-755
    CrossrefPubMedSearch in Google Scholar
  • 22 Chen Z, Foster M W, Zhang J, Mao L, Rockman H A, Kawamoto T, Kitagaw K, Nakayama K I, Hess D T, Stamler J S. An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation.  Proc Natl Acad Sci USA. 2005;  102 12159-12164
    CrossrefPubMedSearch in Google Scholar
  • 23 Wenzel P, Hink U, Oelze M, Schuppan S, Schaeuble K, Schildknecht S, Ho K K, Weniner H, Bachschmid M, Munzel T, Daiber A. Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH‐2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance.  J Biol Chem. 2007;  282 792-799
    PubMedSearch in Google Scholar
  • 24 Daiber A, Oelze M, Sulyok S, Coldewey M, Schulz E, Treiber N, Hink U, Mulsch A, Scharffetter-Kochanek K, Munzel T. Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD±): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.  Mol Pharmacol. 2005;  68 579-588
    PubMedSearch in Google Scholar
  • 25 Wenzel P, Oelze M, Coldewey M, Hortmann M, Seeling A, Hink U, Mollnau H, Stalleicken D, Weiner H, Lehmann J, Li H, Forstermann U, Munzel T, Daiber A. Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.  Arterioscler Thromb Vasc Biol. 2007;  27 1729-1735
    CrossrefPubMedSearch in Google Scholar

Prof. Dr. Guo-Gang Zhang

Department of Cardiovascular Medicine
Xiangya Hospital
Central South University

Changsha

410008 Hunan

People's Republic of China

Phone: + 86 73 14 32 76 95

Fax: + 86 73 14 32 76 95

Email: Guo_gangzhang@yahoo.cn