Annals of Biomedical Engineering

, Volume 41, Issue 10, pp 2193–2205 | Cite as

Transport Limitations of Nitric Oxide Inhibition of Platelet Aggregation under Flow

  • J. L. Sylman
  • S. M. Lantvit
  • M. C. VeDepo
  • M. M. Reynolds
  • K. B. Neeves
Article

Abstract

Nitric oxide (NO) inhibits platelet aggregation at and near the site of a vascular injury by upregulation of cyclic guanosine monophosphate, which reduces the dimerization of the integrin α IIb β 3. The magnitude of NO flux from the vessel wall and the NO concentration that is necessary to inhibit platelet aggregation under physiological flow conditions is unknown. In this study, a NO releasing polymer, diazeniumdiolated dibutylhexanediamine, was integrated into a microfluidic flow assay to determine the relationship between NO wall flux and collagen mediated platelet adhesion, activation and aggregation. A NO flux equal to or greater than 2.5 × 10−10 mol cm−2 min−1 was found to abrogate aggregation, but not initial platelet adhesion, on collagen at 200 and 500 s−1 as effectively as the α IIb β 3 antagonist abciximab. The dynamic range of NO fluxes found to induce measurable inhibition of platelet aggregation spanned from 0.33 × 10−10 to 2.5 × 10−10 mol cm−2 min−1 at 200–500 s−1. These fluxes correspond to near-wall NO concentrations of 3–90 nM based on a computational model of NO transport. The model predicts that NO concentration in the platelet rich layer near the wall is kinetically limited, while NO penetration into the lumen is mass transfer limited.

Keywords

Biotransport Endothelium Hemostasis Thrombosis 

Notes

Acknowledgments

This work was supported by a Scientist Development Grant (K.B.N.) from the American Heart Association, the Colorado Office of Economic Development and International Trade, and the Boettcher Foundation’s Webb-Waring Biomedical Research Award (K.B.N and M.M.R).

Supplementary material

10439_2013_803_MOESM1_ESM.docx (717 kb)
Supplementary material 1 (DOCX 718 kb)

References

  1. 1.
    Antl, M., M. L. von Bruhl, C. Eiglsperger, M. Werner, I. Konrad, T. Kocher, M. Wilm, F. Hofmann, S. Massberg, and J. Schlossmann. IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. Blood 109:552–559, 2007.PubMedCrossRefGoogle Scholar
  2. 2.
    Ballou, D. P., Y. Zhao, P. E. Brandish, and M. A. Marletta. Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: the simple NO-binding model is incorrect. Proc. Natl. Acad. Sci. 99:12097–12101, 2002.PubMedCrossRefGoogle Scholar
  3. 3.
    Batchelor, M. M., S. L. Reoma, P. S. Fleser, V. K. Nuthakki, R. E. Callahan, C. J. Shanley, J. K. Politis, J. Elmore, S. I. Merz, M. E. Meyerhoff. More lipophilic dialkyldiamine-based diazeniumdiolates: synthesis, characterization, and application in preparing thromboresistant nitric oxide release polymeric coatings. J. Med. Chem. 46:5153–5161, 2003.Google Scholar
  4. 4.
    Butler, A. R., I. L. Megson, and P. G. Wright. Diffusion of nitric oxide and scavenging by blood in the vasculature. Biochim. Biophys. Acta 1425:168–176, 1998.PubMedCrossRefGoogle Scholar
  5. 5.
    Condorelli, P., and S. C. George. In vivo control of soluble guanylate cyclase activation by nitric oxide: a kinetic analysis. Biophys. J. 80:2110–2119, 2001.PubMedCrossRefGoogle Scholar
  6. 6.
    Cortese-Krott, M. M., A. Rodriguez-Mateos, R. Sansone, G. G. C. Kuhnle, S. Thasian-Sivarajah, T. Krenz, P. Horn, C. Krisp, D. Wolters, C. Heiss, K. D. Kroncke, N. Hogg, M. Feelisch, and M. Kelm. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease. Blood 120:4229–4237, 2012.PubMedCrossRefGoogle Scholar
  7. 7.
    de Graaf, J. C., J. D. Banga, S. Moncada, R. M. Palmer, P. G. de Groot, and J. J. Sixma. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation 85:2284–2290, 1992.PubMedCrossRefGoogle Scholar
  8. 8.
    Fadel, A. A., K. A. Barbee, and D. Jaron. A computational model of nitric oxide production and transport in a parallel plate flow chamber. Ann. Biomed. Eng. 37:943–954, 2009.PubMedCrossRefGoogle Scholar
  9. 9.
    Freedman, J. E., J. Loscalzo, M. R. Barnard, C. Alpert, J. F. Keaney, and A. D. Michelson. Nitric oxide released from activated platelets inhibits platelet recruitment. J. Clin. Invest. 100:350–356, 1997.PubMedCrossRefGoogle Scholar
  10. 10.
    Hansen, R. R., A. A. Tipnis, T. C. White-Adams, J. A. Di Paola, and K. B. Neeves. Characterization of collagen thin films for von Willebrand factor binding and platelet adhesion. Langmuir 27:13648–13658, 2011.PubMedCrossRefGoogle Scholar
  11. 11.
    Kanai, A. J., H. C. Strauss, G. A. Truskey, A. L. Crews, S. Grunfeld, and T. Malinski. Shear stress induces ATP-independent transient nitric oxide release from vascular endothelial cells, measured directly with a porphyrinic microsensor. Circ. Res. 77:284–293, 1995.PubMedCrossRefGoogle Scholar
  12. 12.
    Kibbe, M., T. Billiar, and E. Tzeng. Inducible nitric oxide synthase and vascular injury. Cardiovasc. Res. 43:650–657, 1999.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim, S., P. K. Ong, O. Yalcin, M. Intaglietta, and P. C. Johnson. The cell-free layer in microvascular blood flow. Biorheology 46:181–189, 2009.PubMedGoogle Scholar
  14. 14.
    Kuchan, M. J., and J. A. Frangos. Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am. J. Physiol. 266:C628–C636, 1994.PubMedGoogle Scholar
  15. 15.
    Malinski, T., Z. Taha, S. Grunfeld, S. Patton, M. Kapturczak, and P. Tomboulian. Diffusion of nitric oxide in the aorta wall monitored in situ by porphyrinic microsensors. Biochem. Biophys. Res. Commun. 193:1076–1082, 1993.PubMedCrossRefGoogle Scholar
  16. 16.
    Mochizuki, S., T. Miyasaka, M. Goto, Y. Ogasawara, T. Yada, M. Akiyama, Y. Neishi, T. Toyoda, J. Tomita, Y. Koyama, K. Tsujioka, F. Kajiya, T. Akasaka, and K. Yoshida. Measurement of acetylcholine-induced endothelium-derived nitric oxide in aorta using a newly developed catheter-type nitric oxide sensor. Biochem. Biophys. Res. Commun. 306:505–508, 2003.PubMedCrossRefGoogle Scholar
  17. 17.
    Nanne, E. E., C. P. Aucoin, and E. F. Leonard. Shear rate and hematocrit effects on the apparent diffusivity of urea in suspensions of bovine erythrocytes. ASAIO J. 56:151–156, 2010.PubMedCrossRefGoogle Scholar
  18. 18.
    Naseem, K. M., and W. Roberts. Nitric oxide at a glance. Platelets 22:148–152, 2011.PubMedCrossRefGoogle Scholar
  19. 19.
    Plata, A. M., S. J. Sherwin, and R. Krams. Endothelial nitric oxide production and transport in flow chambers: the importance of convection. Ann. Biomed. Eng. 38:2805–2816, 2010.PubMedCrossRefGoogle Scholar
  20. 20.
    Ramamurthi, A., and R. S. Lewis. Influence of agonist, shear rate, and perfusion time on nitric oxide inhibition of platelet deposition. Ann. Biomed. Eng. 28:174–181, 2000.PubMedCrossRefGoogle Scholar
  21. 21.
    Roberts, W., A. Michno, A. Aburima, and K. M. Naseem. Nitric oxide inhibits von Willebrand factor-mediated platelet adhesion and spreading through regulation of integrin Π± IIbÎ23and myosin light chain. J. Thromb. Haemost. 7:2106–2115, 2009.PubMedCrossRefGoogle Scholar
  22. 22.
    Roberts, W., R. Riba, S. Homer-Vanniasinkam, R. W. Farndale, and K. M. Naseem. Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagen. J. Thromb. Haemost. 6:2175–2185, 2008.PubMedCrossRefGoogle Scholar
  23. 23.
    Siljander, P., R. W. Farndale, M. A. Feijge, P. Comfurius, S. Kos, E. M. Bevers, and J. W. Heemskerk. Platelet adhesion enhances the glycoprotein VI-dependent procoagulant response: involvement of p38 MAP kinase and calpain. Arterioscler. Thromb. Vasc. Biol. 21:618–627, 2001.PubMedCrossRefGoogle Scholar
  24. 24.
    Skrzypchak, A. M., N. G. Lafayette, R. H. Bartlett, Z. Zhou, M. C. Frost, M. E. Meyerhoff, M. M. Reynolds, and G. M. Annich. Effect of varying nitric oxide release to prevent platelet consumption and preserve platelet function in an in vivo model of extracorporeal circulation. Perfusion 22:193–200, 2007.PubMedCrossRefGoogle Scholar
  25. 25.
    Smith, K. M., L. C. Moore, and H. E. Layton. Advective transport of nitric oxide in a mathematical model of the afferent arteriole. Am. J. Physiol. Renal Physiol. 284:F1080–F1096, 2003.PubMedGoogle Scholar
  26. 26.
    Stone, J. R., and M. A. Marletta. Spectral and kinetic studies on the activation of soluble guanylate cyclase by nitric oxide. Biochemistry 35:1093–1099, 1996.PubMedCrossRefGoogle Scholar
  27. 27.
    Tsoukias, N. M. Nitric oxide bioavailability in the microcirculation: insights from mathematical models. Microcirculation 15:813–834, 2008.PubMedCrossRefGoogle Scholar
  28. 28.
    Tsoukias, N. M., and A. S. Popel. Erythrocyte consumption of nitric oxide in presence and absence of plasma-based hemoglobin. AJP Heart Circ. Physiol. 282:H2265–H2277, 2002.Google Scholar
  29. 29.
    Vaughn, M. W., L. Kuo, and J. C. Liao. Effective diffusion distance of nitric oxide in the microcirculation. Am. J. Physiol. 274:H1705–H1714, 1998.PubMedGoogle Scholar
  30. 30.
    Vaughn, M. W., L. Kuo, and J. C. Liao. Estimation of nitric oxide production and reaction rates in tissue by use of a mathematical model. Am. J. Physiol. 274:H2163–H2176, 1998.PubMedGoogle Scholar
  31. 31.
    Wasserman, S. R., Y. T. Tao, and G. M. Whitesides. Structure and reactivity of alkylsiloxane monolayers formed by reaction of alkyltrichlorosilanes on silicon substrates. Langmuir 5:1074–1087, 1989.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  • J. L. Sylman
    • 1
  • S. M. Lantvit
    • 2
  • M. C. VeDepo
    • 1
  • M. M. Reynolds
    • 2
    • 3
  • K. B. Neeves
    • 1
    • 4
  1. 1.Department of Chemical and Biological EngineeringColorado School of MinesGoldenUSA
  2. 2.Department of ChemistryColorado State UniversityFt. CollinsUSA
  3. 3.School of Biomedical EngineeringColorado State UniversityFt. CollinsUSA
  4. 4.Department of PediatricsUniversity of Colorado DenverAuroraUSA

Personalised recommendations