Cardiovascular Drugs and Therapy

, Volume 20, Issue 3, pp 177–184 | Cite as

Crataegus Special Extract WS® 1442 Induces an Endothelium-Dependent, NO-mediated Vasorelaxation via eNOS-Phosphorylation at Serine 1177

  • Klara Brixius
  • Sonja Willms
  • Andreas Napp
  • Paschalios Tossios
  • Dennis Ladage
  • Wilhelm Bloch
  • Uwe Mehlhorn
  • Robert H. G. SchwingerEmail author
Basic Research



This study investigates the influence of WS® 1442, a special extract of Crataegus leaves with flowers, on the relaxation of rat aorta and human mammarian artery (coronary bypass patients).


Experiments were performed in the presence and absence (mechanical disruption) of endothelium. In addition, we investigated three fractions of WS® 1442 (fraction A: lipophilic, containing flavonoids and oligomeric procyanidins (OPC), fraction B: hydrophilic, containing flavonoids and low molecular weight OPC, fraction C: hydrophilic, essentially flavonoid-free and rich in high molecular weight OPC).


WS® 1442 induced a concentration-dependent vasodilation in isolated vessel rings that had been precontracted by 10 μM phenylephrine (concentration for halfmaximal relaxation (IC50): rat: 15.1 ± 0.6 μg/ml (n = 7), human: 19.3 ± 3.4 μg/ml (n = 6)). The maximal vasorelaxation induced after application of 100 μg of WS® 1442 was 75.0 ± 5.7% (rat) and 79.2 ± 5.8% (human) of the papaverine (0.1 mM)-induced vasodilation. If the experiments were performed in the presence of l-nitroarginine methylester (10 μM, eNOS-inhibition) or after mechanical disruption of the endothelium, no vasorelaxation was observed in the presence of WS® 1442. The vasorelaxant properties of WS® 1442 were mediated by fraction C. WS® 1442 induced an NO-liberation from human coronary artery endothelial cells as measured by diaminofluorescein. WS® 1442 induced eNOS-activation was due to a phosphorylation at serine 1177. No eNOS-translocation or phosphorylation at serine 114 or threonine 495 was observed after application of WS® 1442.


It is concluded that WS® 1442, induces an endothelium-dependent, NO-mediated vasorelaxation via eNOS phosphorylation at serine 1177.

Key words

hawthorn eNOS endothelium human DAF nitric oxide 


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  1. 1.
    Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in the relaxation of arterial smooth muscle by acetycholine. Nature 1980;288:373–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 1987;61:866–79.PubMedGoogle Scholar
  3. 3.
    Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 1988;333:664–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Gray DM, Marshall I. Novel signal transduction pathway mediating endothelium-dependent beta-adrenoceptor vasorelaxation in rat thoracic aorta. Br J Pharmacol 1992;107:684–90.PubMedGoogle Scholar
  5. 5.
    Flemming I, Busse R. Molecular mechanisms involved in the regulation of the edothelial nitric oxide synthase. Am J Physiol 2003;284:R1–12.Google Scholar
  6. 6.
    Llorens S, Jordan J, Nava E. The nitric oxide pathway in the cardiovascular system. J Physiol Biochem 2002;58:179–88.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim SH, Kang KW, Kim KW, Kim ND. Procyanidins in Crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sci 2000;67:121–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen ZY, Zhang ZS, Kwan KY, Zhu M, Ho WKK, Huang Y. Endothelium-dependent relaxation induced by hawthorn extract in rat mesenteric artery. Life Sci 1998;63: 1983–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Schroder D, Weiser M, Klein P. Efficacy of a homeopathic Crataegus preparation compare with usual therapy for mild (NYHA II) cardiac insufficience: results of an observational study. Eur J Heart Failure 2003;5:319–26.CrossRefGoogle Scholar
  10. 10.
    Leuchtgens H. Crataegus-Spezialextrakt WS 1442 bei Herzinsuffizienz NYHA II. Fortschr Med 1993;111:352–4.PubMedGoogle Scholar
  11. 11.
    Weikl A, Assmus K-D, Neukum-Schmidt A, Schmitz J, Zapfe G, Noh HS, et al. Crataegus special extract WS 1442. Assessment of objective effectiveness in patients with heart failure (NYHA II). Fortschr Med 1996;114:291–6.PubMedGoogle Scholar
  12. 12.
    Tauchert M. Efficacy and safety of Crataegus extract WS 1442 in comparison with placeo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J 2002;143:910–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Chatterjee SS, Koch E, Jaggy HEW, Krzeminski T. In vitro und in vivo Untersuchungen zur kardioprotektiven Wirkung von oligomeren Procyanidinen in einem Crataegus-Extrakt (WS 1442) aus Blättern und Blüten. Arzneimittelforschung 1997;47:821–5.PubMedGoogle Scholar
  14. 14.
    Schwinger RHG, Pietsch M, Frank K, Brixius K. Crataegus special extract WS 1442 increases force of contraction in human myocardium cAMP-independently. J Cardiovasc Pharmacol 2000;35:700–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kojima H, Sakurai K, Kikuchi K, Kawahara S, Kirino Y, Nagoshi H, et al. Development of a fluorescent indicator for nitric oxide based on the fluorescein chromophore. Chem Pharm Bull (Tokyo) 1998;46:373–5.Google Scholar
  16. 16.
    Bloch W, Mehlhorn U, Krahwinkel A, Reiner M, Dittrich M, Schmidt A, et al. Ischemia increases detectable endothelial nitric oxide synthase in rat and human myocardium. Nitric Oxide 2001;5:317–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Vierling W, Brand N, Gaedcke F, Sensch KH, Schneider E, Scholz M. Investigation of the pharmaceutical and pharmacological equivalence of different hawthorn extracts. Phytomedicine 2003;10:8–16.PubMedCrossRefGoogle Scholar
  18. 18.
    Fitzpatrick DF, Bing B, Maggi DA, Fleming RC, O'Malley RM. Vasodilating procyanidins derived from grape seeds. Ann N Y Acad Sci 2002;957:78–89.PubMedCrossRefGoogle Scholar
  19. 19.
    Fitzpatrick DF, Bing B, Rohdewald P. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998;32:509–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Corder R, Warburton RC, Khan NQ, Brown RE, Wood EG, Lees DM. The procyanidin-induced pseudo laminar shear stress response: a new concept for the reversal of endothelial dysfunction. Clin Sci (Lond) 2004;107:513–7.CrossRefGoogle Scholar
  21. 21.
    Kenny TP, Keen CL, Jones P, Kung HJ, Schmitz HH, Gershwin ME. Pentameric procyanidins isolated from Theobroma cacao seeds selectively downregulate ErbB2 in human aortic endothelial cells. Exp Biol Med 2004;229:255–63.Google Scholar
  22. 22.
    Waldron GJ, Cole WC. Activation of vascular smooth muscle K+ channels by endothelium-derived relaxing factors. Clin Exp Pharmacol Physiol 1999;26:180–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Walker AF, Marakis G, Morris AP, Robinson PA. Promising hypotensive double-blind pilot study of mild, essential hypertension. Phytother Res 2002;16:48–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Klara Brixius
    • 1
    • 3
  • Sonja Willms
    • 1
  • Andreas Napp
    • 1
  • Paschalios Tossios
    • 2
  • Dennis Ladage
    • 1
  • Wilhelm Bloch
    • 3
  • Uwe Mehlhorn
    • 2
  • Robert H. G. Schwinger
    • 1
    Email author
  1. 1.Laboratory of Muscle Research and Molecular Cardiology, Clinic III for Internal MedicineUniversity of CologneCologneGermany
  2. 2.Clinic of Cardiothoracic SurgeryUniversity of CologneCologneGermany
  3. 3.Department of Molecular and Cellular Sport Medicine, Institute of Cardiology and Sport MedicineGerman Sport University CologneCologneGermany

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