Skip to main content
SpringerLink
Log in

Thymoquinone improves aging-related endothelial dysfunction in the rat mesenteric artery

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Aging-related endothelial dysfunction is characterized by blunted nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations in arteries, which may be due, at least in part, to increased oxidative stress. Endothelial dysfunction will promote the initiation and development of major cardiovascular diseases such as atherosclerosis and hypertension. Thymoquinone (TQ) is the most active constituent of the volatile oil of Nigella sativa seeds with well-documented antioxidative properties and vasodilator effects. This study determined whether TQ improves the endothelial function in middle-aged rats. Control young rats (16 weeks) received solvent (ethanol, 3 % v/v), and middle-aged rats (46 weeks) either solvent or TQ (10 mg/kg/day) in the drinking water. Mesenteric artery reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine and MitoSOX staining, and expression of target proteins by immunohistochemical staining. Aging-related blunted NO- and EDHF-mediated responses were associated with downregulation of endothelial NO synthase (eNOS) and calcium-activated potassium channels (SKCa and IKCa) expression. Endothelial dysfunction was also associated with oxidative stress and an upregulation of angiotensin II and AT1 receptor expressions. Intake of TQ for 14 days restored NO- and EDHF-mediated relaxations, normalized oxidative stress, the expression level of eNOS, SKCa, IKCa, and the components of the angiotensin system in the mesenteric artery of middle-aged rats. Thus, TQ improves endothelial function in aging, at least in part, through inhibition of oxidative stress and normalization of the angiotensin system. TQ may represent a novel therapeutic approach for aging-associated vascular diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Actis-Goretta L, Ottaviani JI, Fraga CG (2006) Inhibition of angiotensin converting enzyme activity by flavanol-rich foods. J Agric Food Chem 54(1):229–234. doi:10.1021/jf052263o

    Article  PubMed  CAS  Google Scholar 

  • Atkinson J, Tatchum-Talom R, Corman B (1994) Effect of chronic Ang I-converting enzyme inhibition on aging processes: III. Endothelial function of mesenteric arterial bed of rat. Am J Physiol 267(1 Pt 2):R136–R143

    PubMed  CAS  Google Scholar 

  • Attia A, Ragheb A, Sylwestrowicz T, Shoker A (2010) Attenuation of high cholesterol-induced oxidative stress in rabbit liver by thymoquinone. Eur J Gastroenterol Hepatol 22(7):826–834. doi:10.1097/MEG.0b013e328336000d

    Article  PubMed  CAS  Google Scholar 

  • Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH (2003) Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 26(2):87–98. doi:10.1081/DCT-120020404

    Article  PubMed  CAS  Google Scholar 

  • Banday AA, Lokhandwala MF (2008) Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension. Am J Physiol Renal Physiol 295(3):F698–F706. doi:10.1152/ajprenal.90308.2008

    Article  PubMed  CAS  Google Scholar 

  • Banday AA, Lokhandwala MF (2011) Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension. Hypertension 57(3):452–459. doi:10.1161/HYPERTENSIONAHA.110.162339

    Article  PubMed  CAS  Google Scholar 

  • Burits M, Bucar F (2000) Antioxidant activity of Nigella sativa essential oil. Phytother Res 14(5):323–328. doi:10.1002/1099-1573(200008)14:5<323::AID-PTR621>3.0.CO;2-Q

    Article  PubMed  CAS  Google Scholar 

  • Butt MS, Sultan MT (2010) Nigella sativa: reduces the risk of various maladies. Crit Rev Food Sci Nutr 50(7):654–665. doi:10.1080/10408390902768797

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Suzuki H, Weston AH (1988) Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br J Pharmacol 95(4):1165–1174

    PubMed  CAS  Google Scholar 

  • Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90(11):1159–1166

    Article  PubMed  CAS  Google Scholar 

  • Dal-Ros S, Oswald-Mammosser M, Pestrikova T, Schott C, Boehm N, Bronner C, Chataigneau T, Geny B, Schini-Kerth VB (2010) Losartan prevents portal hypertension-induced, redox-mediated endothelial dysfunction in the mesenteric artery in rats. Gastroenterology 138(4):1574–1584. doi:10.1053/j.gastro.2009.10.040

    Article  PubMed  CAS  Google Scholar 

  • Dal-Ros S, Zoll J, Lang AL, Auger C, Keller N, Bronner C, Geny B, Schini-Kerth VB (2011) Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: role of NADPH oxidase. Biochem Biophys Res Commun 404(2):743–749. doi:10.1016/j.bbrc.2010.12.060

    Article  PubMed  CAS  Google Scholar 

  • Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR (2007) Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 100(11):1659–1666. doi:10.1161/01.RES.0000269183.13937.e8

    Article  PubMed  CAS  Google Scholar 

  • Dong J, Xu X, Liang Y, Head R, Bennett L (2011) Inhibition of angiotensin converting enzyme (ACE) activity by polyphenols from tea (Camellia sinensis) and links to processing method. Food Funct 2(6):310–319. doi:10.1039/c1fo10023h

    Article  PubMed  CAS  Google Scholar 

  • Edwards G, Feletou M, Weston AH (2010) Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch 459(6):863–879. doi:10.1007/s00424-010-0817-1

    Article  PubMed  CAS  Google Scholar 

  • Feletou M, Vanhoutte PM (2006) Endothelial dysfunction: a multifaceted disorder (the Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291(3):H985–H1002. doi:10.1152/ajpheart.00292.2006

    Article  PubMed  CAS  Google Scholar 

  • Flammer AJ, Luscher TF (2010) Three decades of endothelium research: from the detection of nitric oxide to the everyday implementation of endothelial function measurements in cardiovascular diseases. Swiss Med Wkly 140:w13122. doi:10.4414/smw.2010.13122

    PubMed  Google Scholar 

  • Fouda AM, Daba MH, Dahab GM, Sharaf El-Din OA (2008) Thymoquinone ameliorates renal oxidative damage and proliferative response induced by mercuric chloride in rats. Basic Clin Pharmacol Toxicol 103(2):109–118. doi:10.1111/j.1742-7843.2008.00260.x

    Article  PubMed  CAS  Google Scholar 

  • Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, Pelicci PG, Schiavoni M, Luscher TF, Volpe M, Cosentino F (2004) Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation 110(18):2889–2895. doi:10.1161/01.CIR.0000147731.24444.4D

    Article  PubMed  CAS  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288(5789):373–376

    Article  PubMed  CAS  Google Scholar 

  • Goto K, Fujii K, Onaka U, Abe I, Fujishima M (2000) Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction. Hypertension 36(4):581–587

    PubMed  CAS  Google Scholar 

  • Goto K, Fujii K, Kansui Y, Iida M (2004) Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with renin–angiotensin system inhibitors. Clin Exp Pharmacol Physiol 31(9):650–655. doi:10.1111/j.1440-1681.2004.04054.x

    Article  PubMed  CAS  Google Scholar 

  • Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106(6):653–658

    Article  PubMed  Google Scholar 

  • Herrera MD, Mingorance C, Rodriguez-Rodriguez R, Alvarez de Sotomayor M (2010) Endothelial dysfunction and aging: an update. Ageing Res Rev 9(2):142–152. doi:10.1016/j.arr.2009.07.002

    Article  PubMed  CAS  Google Scholar 

  • Hilgers RH, Webb RC (2007) Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 292(5):H2275–H2284. doi:10.1152/ajpheart.00949.2006

    Article  PubMed  CAS  Google Scholar 

  • Hongo K, Nakagomi T, Kassell NF, Sasaki T, Lehman M, Vollmer DG, Tsukahara T, Ogawa H, Torner J (1988) Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke 19(7):892–897

    Article  PubMed  CAS  Google Scholar 

  • Idris Khodja N, Chataigneau T, Auger C, Schini-Kerth VB (2012) Grape-derived polyphenols improve aging-related endothelial dysfunction in rat mesenteric artery: role of oxidative stress and the angiotensin system. PLoS One 7(2):e32039. doi:10.1371/journal.pone.0032039

    Article  PubMed  Google Scholar 

  • Jung FF, Kennefick TM, Ingelfinger JR, Vora JP, Anderson S (1995) Down-regulation of the intrarenal renin–angiotensin system in the aging rat. J Am Soc Nephrol 5(8):1573–1580

    PubMed  CAS  Google Scholar 

  • Kansui Y, Fujii K, Goto K, Abe I, Iida M (2002) Angiotensin II receptor antagonist improves age-related endothelial dysfunction. J Hypertens 20(3):439–446

    Article  PubMed  CAS  Google Scholar 

  • Khattab MM, Nagi MN (2007) Thymoquinone supplementation attenuates hypertension and renal damage in nitric oxide deficient hypertensive rats. Phytother Res 21(5):410–414. doi:10.1002/ptr.2083

    Article  PubMed  CAS  Google Scholar 

  • Knorr M, Hausding M, Kroller-Schuhmacher S, Steven S, Oelze M, Heeren T, Scholz A, Gori T, Wenzel P, Schulz E, Daiber A, Munzel T (2011) Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-glutathionylation of endothelial nitric oxide synthase: beneficial effects of therapy with the AT1 receptor blocker telmisartan. Arterioscler Thromb Vasc Biol 31(10):2223–2231. doi:10.1161/ATVBAHA.111.232058

    Article  PubMed  CAS  Google Scholar 

  • Krummen S, Drouin A, Gendron ME, Falck JR, Thorin E (2006) ROS-sensitive cytochrome P450 activity maintains endothelial dilatation in ageing but is transitory in dyslipidaemic mice. Br J Pharmacol 147(8):897–904. doi:10.1038/sj.bjp.0706679

    Article  PubMed  CAS  Google Scholar 

  • Lavrentyev EN, Estes AM, Malik KU (2007) Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells. Circ Res 101(5):455–464. doi:10.1161/CIRCRESAHA.107.151852

    Article  PubMed  CAS  Google Scholar 

  • Lesniewski LA, Connell ML, Durrant JR, Folian BJ, Anderson MC, Donato AJ, Seals DR (2009) B6D2F1 Mice are a suitable model of oxidative stress-mediated impaired endothelium-dependent dilation with aging. J Gerontol A Biol Sci Med Sci 64(1):9–20. doi:10.1093/gerona/gln049

    Article  PubMed  Google Scholar 

  • Li JM, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287(5):R1014–R1030. doi:10.1152/ajpregu.00124.2004

    Article  PubMed  CAS  Google Scholar 

  • Long DA, Newaz MA, Prabhakar SS, Price KL, Truong LD, Feng L, Mu W, Oyekan AO, Johnson RJ (2005) Loss of nitric oxide and endothelial-derived hyperpolarizing factor-mediated responses in aging. Kidney Int 68(5):2154–2163. doi:10.1111/j.1523-1755.2005.00671.x

    Article  PubMed  CAS  Google Scholar 

  • Matz RL, de Sotomayor MA, Schott C, Stoclet JC, Andriantsitohaina R (2000) Vascular bed heterogeneity in age-related endothelial dysfunction with respect to NO and eicosanoids. Br J Pharmacol 131(2):303–311. doi:10.1038/sj.bjp.0703568

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki R, Ichiki T, Hashimoto T, Inanaga K, Imayama I, Sadoshima J, Sunagawa K (2008) SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 28(7):1263–1269. doi:10.1161/ATVBAHA.108.166991

    Article  PubMed  CAS  Google Scholar 

  • Modrick ML, Didion SP, Sigmund CD, Faraci FM (2009) Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol 296(6):H1914–H1919. doi:10.1152/ajpheart.00300.2009

    Article  PubMed  CAS  Google Scholar 

  • Mukai Y, Shimokawa H, Higashi M, Morikawa K, Matoba T, Hiroki J, Kunihiro I, Talukder HM, Takeshita A (2002) Inhibition of renin–angiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol 22(9):1445–1450

    Article  PubMed  CAS  Google Scholar 

  • Munzel T, Daiber A, Ullrich V, Mulsch A (2005) Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 25(8):1551–1557. doi:10.1161/01.ATV.0000168896.64927.bb

    Article  PubMed  Google Scholar 

  • Nagi MN, Al-Shabanah OA, Hafez MM, Sayed-Ahmed MM (2011) Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. J Biochem Mol Toxicol 25(3):135–142. doi:10.1002/jbt.20369

    Article  PubMed  CAS  Google Scholar 

  • Nakashima M, Mombouli JV, Taylor AA, Vanhoutte PM (1993) Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries. J Clin Invest 92(6):2867–2871. doi:10.1172/JCI116907

    Article  PubMed  CAS  Google Scholar 

  • Oelze M, Daiber A, Brandes RP, Hortmann M, Wenzel P, Hink U, Schulz E, Mollnau H, von Sandersleben A, Kleschyov AL, Mulsch A, Li H, Forstermann U, Munzel T (2006) Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats. Hypertension 48(4):677–684. doi:10.1161/01.HYP.0000239207.82326.29

    Article  PubMed  CAS  Google Scholar 

  • Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526. doi:10.1038/327524a0

    Article  PubMed  CAS  Google Scholar 

  • Persson IA, Persson K, Andersson RG (2009) Effect of Vaccinium myrtillus and its polyphenols on angiotensin-converting enzyme activity in human endothelial cells. J Agric Food Chem 57(11):4626–4629. doi:10.1021/jf900128s

    Article  PubMed  CAS  Google Scholar 

  • Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A (2009) The protective effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl 20(5):741–752

    PubMed  Google Scholar 

  • Rees DD, Palmer RM, Hodson HF, Moncada S (1989) A specific inhibitor of nitric oxide formation from l-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol 96(2):418–424

    PubMed  CAS  Google Scholar 

  • Rivas-Arreola MJ, Rocha-Guzman NE, Gallegos-Infante JA, Gonzalez-Laredo RF, Rosales-Castro M, Bacon JR, Cao R, Proulx A, Intriago-Ortega P (2010) Antioxidant activity of oak (Quercus) leaves infusions against free radicals and their cardioprotective potential. Pak J Biol Sci 13(11):537–545

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Manas L, El-Assar M, Vallejo S, Lopez-Doriga P, Solis J, Petidier R, Montes M, Nevado J, Castro M, Gomez-Guerrero C, Peiro C, Sanchez-Ferrer CF (2009) Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell 8(3):226–238. doi:10.1111/j.1474-9726.2009.00466.x

    Article  PubMed  CAS  Google Scholar 

  • Sankaranarayanan C, Pari L (2011) Thymoquinone ameliorates chemical induced oxidative stress and beta-cell damage in experimental hyperglycemic rats. Chem Biol Interact 190(2–3):148–154. doi:10.1016/j.cbi.2011.02.029

    Article  PubMed  CAS  Google Scholar 

  • Sarr M, Chataigneau M, Martins S, Schott C, El Bedoui J, Oak MH, Muller B, Chataigneau T, Schini-Kerth VB (2006) Red wine polyphenols prevent angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase. Cardiovasc Res 71(4):794–802. doi:10.1016/j.cardiores.2006.05.022

    Article  PubMed  CAS  Google Scholar 

  • Sayed-Ahmed MM, Aleisa AM, Al-Rejaie SS, Al-Yahya AA, Al-Shabanah OA, Hafez MM, Nagi MN (2010) Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxid Med Cell Longev 3(4):254–261

    Article  PubMed  Google Scholar 

  • Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101(16):1899–1906

    PubMed  CAS  Google Scholar 

  • Suddek GM (2010) Thymoquinone-induced relaxation of isolated rat pulmonary artery. J Ethnopharmacol 127(2):210–214. doi:10.1016/j.jep.2009.11.019

    Article  PubMed  CAS  Google Scholar 

  • Tesarova H, Svobodova B, Kokoska L, Marsik P, Pribylova M, Landa P, Vadlejch J (2011) Determination of oxygen radical absorbance capacity of black cumin (Nigella sativa) seed quinone compounds. Nat Prod Commun 6(2):213–216

    PubMed  CAS  Google Scholar 

  • Ungvari Z, Sonntag WE, Csiszar A (2010) Mitochondria and aging in the vascular system. J Mol Med (Berl) 88(10):1021–1027. doi:10.1007/s00109-010-0667-5

    Article  CAS  Google Scholar 

  • Urakami-Harasawa L, Shimokawa H, Nakashima M, Egashira K, Takeshita A (1997) Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 100(11):2793–2799. doi:10.1172/JCI119826

    Article  PubMed  CAS  Google Scholar 

  • van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF (2000) Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med 192(12):1731–1744

    Article  PubMed  Google Scholar 

  • Vanhoutte PM (2009) How we learned to say no. Arterioscler Thromb Vasc Biol 29(8):1156–1160. doi:10.1161/ATVBAHA.109.190215

    Article  PubMed  CAS  Google Scholar 

  • Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196(2):193–222. doi:10.1111/j.1748-1716.2009.01964.x

    Article  CAS  Google Scholar 

  • Wenzel P, Schuhmacher S, Kienhofer J, Muller J, Hortmann M, Oelze M, Schulz E, Treiber N, Kawamoto T, Scharffetter-Kochanek K, Munzel T, Burkle A, Bachschmid MM, Daiber A (2008) Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc Res 80(2):280–289. doi:10.1093/cvr/cvn182

    Article  PubMed  CAS  Google Scholar 

  • Widlansky ME, Gokce N, Keaney JF Jr, Vita JA (2003) The clinical implications of endothelial dysfunction. J Am Coll Cardiol 42(7):1149–1160

    Article  PubMed  CAS  Google Scholar 

  • Wu S, Ruan Y, Yin M, Lai W (2007) Research on the age-related changes in the nitric oxide pathway in the arteries of rats and the intervention effect of dehydroepiandrosterone. Gerontology 53(4):234–237. doi:10.1159/000100961

    Article  PubMed  CAS  Google Scholar 

  • Yu MA, Sanchez-Lozada LG, Johnson RJ, Kang DH (2010) Oxidative stress with an activation of the renin–angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens 28(6):1234–1242

    PubMed  Google Scholar 

  • Zanetti M, Gortan Cappellari G, Burekovic I, Barazzoni R, Stebel M, Guarnieri G (2010) Caloric restriction improves endothelial dysfunction during vascular aging: effects on nitric oxide synthase isoforms and oxidative stress in rat aorta. Exp Gerontol 45(11):848–855. doi:10.1016/j.exger.2010.07.002

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CNRS UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Faculty of Pharmacy, University of Strasbourg, 74, route du Rhin, BP 60024, 67401, Illkirch, France

    Noureddine Idris-Khodja & Valérie Schini-Kerth

Authors
  1. Noureddine Idris-Khodja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valérie Schini-Kerth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valérie Schini-Kerth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Idris-Khodja, N., Schini-Kerth, V. Thymoquinone improves aging-related endothelial dysfunction in the rat mesenteric artery. Naunyn-Schmiedeberg's Arch Pharmacol 385, 749–758 (2012). https://doi.org/10.1007/s00210-012-0749-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-012-0749-8

Keywords

Search

Navigation