Journal of Chemical Biology

, Volume 7, Issue 2, pp 57–65 | Cite as

Gold nanoparticle modifies nitric oxide release and vasodilation in rat aorta

  • Bruno R. Silva
  • Claure N. Lunardi
  • Koiti Araki
  • Juliana C. Biazzotto
  • Roberto S. Da Silva
  • Lusiane M. Bendhack
Original Article


Nitric oxide (NO) plays an important role on several biological functions. Recently, it has been reported the possibility of modifying the NO release profile from the NO donors through its coupling to gold nanoparticles (AuNPs). Thus, AuNPs were synthesized and they were exposed to the NO donor ruthenium complex Cis-[Ru(bpy)2(NO)(4PySH)].(PF6)3 termed (Ru-4PySH)—forming AuNPs-{Ru-4PySH}n cluster. Our results indicate that AuNPs do not modify the maximum effect (ME) and potency (pD2) in the vasodilation induced by Ru-4PySH. Both complexes induce similar vascular relaxation in concentration-dependent way. However, the NO released from the complex AuNPs-{Ru-4PySH}n is lower than Ru-4PySH. Both complexes release only NO0 specie, but AuNPs-{Ru-4PySH}n releases NO in constant way and exclusively in the extracellular medium. In time-course, Ru-4Py-SH was faster than AuNPs-{Ru-4PySH}n in inducing the maximum vasodilation. Inhibition of soluble guanylyl cyclase (sGC) abolished the vasodilation induced by Ru-4PYSH, but not by AuNPs-{Ru-4PySH}n. Non-selective potassium (K+) channel blocker TEA had no effect on the vasodilation induced by AuNPs-{Ru-4PySH}n, but it reduced the potency to Ru-4PySH. In conclusion, our results suggest that AuNPs can reduce the permeability of NO donor Ru-4PySH due to AuNPs-{Ru-4PySH}n cluster formation. AuNPs reduce NO release, but they do not impair the vasodilator effect induced by the NO donor. Ru-4PySH induces vasodilation by sGC and K+ channels activation, while AuNPs-{Ru-4PySH}n activates mainly sGC. Taken together, these findings represent a new pharmacological strategy to control the NO release which could activate selective biological targets.


Gold nanoparticle Vasodilation Nitric oxide (NO) NO donor ruthenium complex Soluble guanylyl cyclase Potassium channels 


  1. 1.
    Gao Y (2010) The multiple actions of NO. Pflugers Arch - Eur J Physiol 459:829–839CrossRefGoogle Scholar
  2. 2.
    Ignarro LJ, Ballot B, Wood KS (1984) Regulation of soluble guanylate cyclase activity by phorpyrins and metallophorpyrins. J Biol Chem 259:6201–6207Google Scholar
  3. 3.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84:9265–9269CrossRefGoogle Scholar
  4. 4.
    Ignarro LJ (1989) Endothelium-derived nitric oxide pharmacology and relationship to the actions of organic nitrate esters. Pharm Res 6:651–659CrossRefGoogle Scholar
  5. 5.
    Moncada S, Palmer RMJ, Gryglewski RJ (1986) Mechanism of action of some inhibitors of endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 83:9164–9168CrossRefGoogle Scholar
  6. 6.
    Lohse MJ, Forstermann U, Schmitt HHHW (1998) Pharmacology of NO: cGMP signal transduction. Naunyn-Schmiedeberg's Arch Pharmacol 358:111–112CrossRefGoogle Scholar
  7. 7.
    Bolotina V, Najibi S, Palacino JJ, Pagano PJ, Cohen RA (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368:850–853CrossRefGoogle Scholar
  8. 8.
    Homer KL, Wanstall JC (2000) Cyclic GMP- independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor. Br J Pharmacol 131:673–682CrossRefGoogle Scholar
  9. 9.
    Bateman RM, Sharpe MD, Ellis CG (2003) Bench-to-bedside review: microvascular dysfunction in sepsis–hemodynamics, oxygen transport, and nitric oxide. Crit Care 7:359–373CrossRefGoogle Scholar
  10. 10.
    Higashi Y, Noma K, Yoshizumi M, Kihara Y (2009) Endothelial function and oxidative stress in cardiovascular diseases. Circ J 73:411–418CrossRefGoogle Scholar
  11. 11.
    Bonaventura D, De Lima RG, Vercesi JA, Da Silva RS, Bendhack LM (2007) Comparison of the mechanisms underlying the relaxation induced by two nitric oxide donors: sodium nitroprusside and new ruthenium complex. Vasc Pharmacol 46:215–222CrossRefGoogle Scholar
  12. 12.
    Ferrari M (2005) Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer 5:161–171CrossRefGoogle Scholar
  13. 13.
    Connor EE, Mwamuka J, Gole A, Murphy CJ, Wyatt MD (2005) Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1:325–327CrossRefGoogle Scholar
  14. 14.
    Rothrock AR, Donkers RL, Schoenfisch MH (2005) Synthesis of nitric oxide-releasing gold nanoparticles. J Am Chem Soc 127:9362–9363CrossRefGoogle Scholar
  15. 15.
    Polizzi MA, Stasko NA, Schoenfisch MH (2007) Water-soluble nitric oxide-releasing gold nanoparticles. Langmuir 23:4938–4943CrossRefGoogle Scholar
  16. 16.
    Diaz-Garcia AM, Fernández-Oliva M, Ortiz M, Cão R (2009) Interaction of nitric oxide with gold nanoparticles capped with a ruthenium (II) complex. Dalton Trans 7870–7872Google Scholar
  17. 17.
    Bonaventura D, De Oliveira FS, Togniolo V, Tedesco AC, Da Silva RS, Bendhack LM (2004) A macrocyclic nitrosyl ruthenium complex is a NO donor that induces rat aorta relaxation. Nitric Oxide 10:83–91CrossRefGoogle Scholar
  18. 18.
    Bonaventura D, De Oliveira FS, Da Silva RS, Bendhack LM (2005) Decreased vasodilation induced by a new nitric oxide donor in two kidney, one clip hypertensive rats is due to impaired K+ channel activation. Clin Exp Pharmacol Physiol 32:478–481CrossRefGoogle Scholar
  19. 19.
    Da Rocha ZN, Marchesi MSP, Molin JC, Lunardi CN, Miranda KM, Bendhack LM, Ford PC, Da Silva RS (2008) The inducing NO-vasodilation by chemical reduction of coordinated nitrite ion in cis-[Ru(NO2)L(bpy)2]+ complex. Dalton Trans 4282–4287Google Scholar
  20. 20.
    Pereira AC, Ford PC, Da Silva RS, Bendhack LM (2011) Ruthenium-nitrite complex as pro-drug releases NO in a tissue and enzyme-dependent way. Nitric Oxide 24:192–198CrossRefGoogle Scholar
  21. 21.
    Rodrigues GJ, Lunardi CN, Lima RG, Santos CX, Laurindo FRM, Da Silva RS, Bendhack LM (2008) Vitamin C improves the effect of a new nitric oxide donor on the vascular smooth muscle from renal hypertensive rats. Nitric Oxide 18:176–183CrossRefGoogle Scholar
  22. 22.
    Kudo S, Bourassa JL, Boggs SE, Sato Y, Ford PC (1997) In situ nitric oxide (NO) measurement by modified electrodes: NO labilized by photolysis of metal nitrosyl complexes. Anal Biochem 247:193–202CrossRefGoogle Scholar
  23. 23.
    Mori V, Bertotti M (2000) Nitric oxide solutions: standardisation bychronoamperometry using a platinum disc microelectrode. Analyst 125:1629–1632CrossRefGoogle Scholar
  24. 24.
    Wink DA, Darbyshire JF, Nims RW, Saavedra JE, Ford PC (1993) Reactions of the bioregulatory agent nitric-oxide in oxygenated aqueous-media: determination of the kinetics for oxidation and nitrosation by intermediates generated in the NO/O2 reaction. Chem Res Toxicol 6:23–27CrossRefGoogle Scholar
  25. 25.
    Sauaia MG, Oliveira FS, De Lima RG, Cacciari AL, Tfouni E, Da Silva RS (2005) Syntheses, characterization and photochemical properties of new NO0–ruthenium(II) complexes. Inorg Chem Commun 347–349Google Scholar
  26. 26.
    Kimling J, Maier M, Okenve B, Kotaidis V, Ballot H, Plech A (2006) Turkevich method for gold nanoparticle synthesis revisited. J Phys Chem B 110:15700–15707CrossRefGoogle Scholar
  27. 27.
    Jadzinsky PD, Calero G, Ackerson CJ, Bushnell DA, Kornberg RD (2007) Structure of a thiol monolayer-protected gold nanoparticle at 1.1 Å resolution. Science 318:430–433CrossRefGoogle Scholar
  28. 28.
    Martin W, Villani GM, Jothianandan D, Furchgott RF (1985) Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther 232:708–716Google Scholar
  29. 29.
    Bonaventura D, Oliveira FS, Lunardi CN, Vercesi JA, Da Silva RS, Bendhack LM (2006) Characterization of the mechanisms of action and nitric oxide species involved in the relaxation induced by the ruthenium complex. Nitric Oxide 15:387–394CrossRefGoogle Scholar
  30. 30.
    Bordini J, Hughes DL, Neto JDM, Da Cunha CJ (2002) Nitric oxide photorelease from ruthenium salen complexes in aqueous and organic solutions. Inorg Chem 41:5410–5416CrossRefGoogle Scholar
  31. 31.
    Kayser O, Lemke A, Hernandez-Trejo N (2005) The impact of nanobiotechnology on the development of new drug delivery systems. Curr Pharm Biotechnol 6:3–5Google Scholar
  32. 32.
    Mieszawska AJ, Mulder WJM, Fayad ZA, Cormode DP (2013) Multifunctional gold nanoparticles for diagnosis and therapy of disease. Mol Pharm 10:831–847CrossRefGoogle Scholar
  33. 33.
    Huang X, Brazel CS (2001) On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release 73:121–136CrossRefGoogle Scholar
  34. 34.
    De Figueiredo LF, Nelson SH, Mathru M, Silva MR, Kramer GC (2001) Effects of hemoglobin-based blood substitutes on vasoactivity of rat aortic rings. Artif Organs 25:928–933CrossRefGoogle Scholar
  35. 35.
    Soloviev A, Lehen'kyi V, Zelensky S, Hellstrand P (2004) Nitric oxide relaxes rat tail artery smooth muscle by cyclic GMP-independent decrease in calcium sensitivity of myofilaments. Cell Calcium 36:165–173CrossRefGoogle Scholar
  36. 36.
    Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA (2008) The chemical biology of nitric oxide: implications in cellular signaling. Free Radic Biol Med 45:18–31CrossRefGoogle Scholar
  37. 37.
    Wanstall JC, JeVery TK, Gambino A, Lovren F, Triggle CR (2001) Vascular smooth muscle relaxation mediated by nitric oxide donors: a comparison with acetylcholine, nitric oxide and nitroxyl ion. Br J Pharmacol 134:463–472CrossRefGoogle Scholar
  38. 38.
    Hall CN, Garthwaite J (2009) What is the real physiological NO concentration in vivo? Nitric Oxide 21:92–103CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Bruno R. Silva
    • 1
    • 5
    • 6
  • Claure N. Lunardi
    • 2
  • Koiti Araki
    • 3
  • Juliana C. Biazzotto
    • 4
  • Roberto S. Da Silva
    • 4
  • Lusiane M. Bendhack
    • 5
  1. 1.Department of Pharmacology, School of Medicine of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  2. 2.Faculty of CeilândiaUniversity of BrasiliaBrasíliaBrazil
  3. 3.Institute of ChemistryUniversity of São PauloSão PauloBrazil
  4. 4.Laboratory of Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  5. 5.Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão PretoUniversity of São PauloSão PauloBrazil
  6. 6.Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil

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