Endophytic Fungal Metabolite Fumigaclavine C Causes Relaxation of Isolated Rat Aortic Rings

Abstract

Two indole alkaloids were isolated from the culture of Aspergillus fumigatus (strain No. CY018), an endophytic fungus harboring inside the elder leaf of Cynodon dactylon. These two chemicals were identified as fumigaclavine C and fumitremorgin C. In screening the bioactivity of these two indole alkaloids, their vasorelaxant effects on isolated rat thoracic aortic rings were observed. The results showed that fumigaclavine C exhibited potent concentration-dependent vasorelaxant actions in isolated rat aortic rings pre-contracted by high K⁺ or phenylephrine (with EC₅₀ values of 5.62 μmol/L and 1.58 μmol/L, respectively) whereas fumitremorgin C displayed a weaker vasorelaxation. A detailed investigation was therefore performed with fumigaclavine C. The vasorelaxing action of fumigaclavine C is independent of the presence of endothelium, suggesting its effect of vasorelaxation was not related to endothelial mediators. Blockage of L-type voltage-dependent calcium channels, activation of ATP-sensitive potassium channels and inhibition of Ca²⁺ release from intracellular Ca²⁺ stores may be involved in fumigaclavine C induced relaxation of rat isolated aortic rings. These results demonstrate that fumigaclavine C from the endophytic fungus has a potential capacity in vascular protection and thus may have therapeutic use in protection against cardiovascular disease.

Fumigaclavine C - Aspergillus fumigatus - endophyte - vasorelaxation

References

• 1 Tan R X, Zou W X. Endophytes, a rich source of functional metabolites.  Nat Prod Rep. 2001;  18 448-59
• 2 Lu H, Zou W X, Meng J C, Hu J, Tan R X. New bioactive metabolites produced by Colletotrichum sp., an endophytic fungus in Artemisia annua .  Plant Sci. 2000;  151 67-73
• 3 Zou W X, Meng J C, Lu H, Chen G X, Shi G X, Zhang T Y. et al . Metabolites of Colletotrichum gloeosporioides, an endophytic fungus in Artemisia mongolica .  J Nat Prod. 2000;  63 1529-30
• 4 Liu J Y, Liu C H, Zou W X, Tian X, Tan R X. Leptosphaerone, a metabolite with a novel skeleton from Leptosphaeria sp. IV403, an endophytic fungus in Artemisia annua .  Helv Chim Acta. 2002;  85 2664-7
• 5 Liu J Y, Song Y C, Zhang Z, Wang L, Guo Z J, Zou W X. et al . Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites.  J Biotechnol. 2004;  114 279-87
• 6 Xie Z W, Fan C S, Zhu Z Y. Atlas of National Traditional Chinese Medicinal Herbs, Book II. 2nd edn Beijing; People’s Hygiene Press 1996: pp 505-6
• 7 Zhao Y, Liu J, Wang J, Wang L, Yin H, Tan R. et al . Fumigaclavine C improves concanavalin A-induced liver injury in mice mainly via inhibiting TNF-alpha production and lymphocyte adhesion to extracellular matrices.  J Pharm Pharmacol. 2004;  56 775-82
• 8 Cole R J, Kirksey J W, Dorner J W, Wilson D V, Johnson J C, Johnson A N. et al . Mycotoxins produced by Aspergillus fumigatus species isolated from molded silage.  J Agric Food Chem. 1977;  25 826-30
• 9 Cole R J, Cox R H. Handbook of toxic fungal metabolites I. New York; Academic Press 1981: p 364
• 10 Liu C H, Zou W X, Lu H, Tan R X. Antifungal activity of Artemisia annua endophyte cultures against phytopathogenic fungi.  J Biotechnol. 2001;  88 277-82
• 11 Raper K E, Fennell D I. The Genus Aspergillus . Baltimore; The Williams and Wilkins Co 1965: p 239
• 12 Frisvad J C, Samson R A. Chemotaxonomy and morphology of Aspergillus fumigatus and related taxa. In: Samson RA, Pin JI, editors Modern concepts in Penicillum and Aspergillus classification. New York; Plenum Press 1990: pp 201-8
• 13 McGuire J J, Ding H, Triggle C R. Endothelium-derived relaxing factors: a focus on endothelium-derived hyperpolarizing factor(s).  Can J Physiol Pharmacol. 2001;  79 443-70
• 14 Somlyo A P, Somlyo A V. Signal transduction and regulation in smooth muscle.  Nature. 1994;  372 231-6
• 15 Schramm M, Thomas G, Towart R, Franckowiak G. Novel dihydropyridines with positive inotropic action through activation of Ca²⁺ channels.  Nature. 1983;  303 535-7
• 16 Hof R P, Vuorela H J. Assessing calcium antagonism on vascular smooth muscle: a comparison of three methods.  J Pharmacol Methods. 1983;  9 41-52
• 17 Hagiwara S, Mitsui M, Karaki H. Effects of felodipine, nifedipine and verapamil on cytosolic Ca²⁺ and contraction in vascular smooth muscle.  Eur J Pharmacol. 1993;  234 1-7
• 18 Nelson M T, Quayle J M. Physiological roles and properties of potassium channels in arterial smooth muscle.  Am J Physiol. 1995;  268 C799-822
• 19 Brady S F, Wagenaar M M, Singh M P, Janso J E, Clardy J. The cytosporones, new octaketide antibiotics isolated from an endophytic fungus.  Org Lett. 2000;  2 4043-6
• 20 Yue Q, Miller C J, White JF J r, Richardson M D. Isolation and characterization of fungal inhibitors from Epichloe festucae .  J Agric Food Chem. 2000;  48 4687-92
• 21 Sharma S K, Jia G, Lown J W. Novel cyclopropylindole conjugates and dimers: synthesis and anti-cancer evaluation.  Curr Med Chem Anti-Cancer Agents. 2001;  1 27-45
• 22 Katayama S, Ae N, Kodo T, Masumoto S, Hourai S, Tamamura C. et al . Tricyclic indole-2-carboxylic acids: highly in vivo active and selective antagonists for the glycine binding site of the NMDA receptor.  J Med Chem. 2003;  46 691-701
• 23 Iwata S, Saito S, Kon-Ya K, Shizuri Y, Ohizumi Y. Novel marine-derived halogen-containing gramine analogues induce vasorelaxation in isolated rat aorta.  Eur J Pharmacol. 2001;  432 63-70