title: Transport limitations of nitric oxide inhibition of platelet aggregation under flow.
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)β₃. 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)β₃ 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.
authors.affiliation: Department of Chemical and Biological Engineering, Colorado School of Mines, 1600 Illinois Street, Golden, CO 80401, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Sylman
authors.forename: S M
authors.initials: SM
authors.lastname: Lantvit
authors.forename: M C
authors.initials: MC
authors.lastname: Vedepo
authors.forename: M M
authors.initials: MM
authors.lastname: Reynolds
authors.forename: K B
authors.initials: KB
authors.lastname: Neeves
mesh_terms: D001391:Azo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D001783:Blood Flow Velocity; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D046210:Microfluidic Analytical Techniques; D008954:Models, Biological; D009569:Nitric Oxide / Q000493:pharmacokinetics* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*
chemical_list: D001391:Azo Compounds; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C452539:diazeniumdiolate; D009569:Nitric Oxide