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Enhanced release of nitric oxide causes increased cytotoxicity of S-nitroso-N-acetyl-DL-penicillamine and sodium nitroprusside under hypoxic conditions.

ABSTRACT: S-Nitroso-N-acetyl-DL-penicillamine (SNAP) and sodium nitroprusside (SNP), both of which are known to release nitric oxide (.NO), exhibited cytotoxicity against cultivated endothelial cells. Under hypoxic conditions 5 mM SNAP and 20 mM SNP induced a loss in cell viability of about 90% and 80% respectively, after an 8 h incubation. Under normoxic conditions, cell death was only 45% and 42% respectively within the same time period. Concentrations of .NO liberated from SNAP and SNP were measured by the oxyhaemoglobin method and by two of the recently developed nitric oxide cheletropic traps (NOCTs). The .NO concentrations from SNAP and SNP increased from 74 microM and 28 microM to 136 microM and 66 microM respectively within 15 min of hypoxic incubation, and then decreased to 36 microM and 28 microM. In the respective normoxic incubations the .NO levels from SNAP and SNP remained in the region of about 30 microM and 20 microM respectively. In contrast, spermine/NO adduct (spermineNONOate) was shown to be more toxic under normoxic than under hypoxic conditions. Under either of these conditions, the concentration of .NO liberated from 2 mM spermineNONOate was about 20 microM. The results demonstrate that the cytotoxicity of SNAP and SNP, but not of spermineNONOate, is significantly enhanced under hypoxic compared with normoxic incubations. Studies on the .NO-releasing behaviour of these compounds indicate that the increased toxicity of SNAP and SNP under hypoxic conditions is related to the influence of O2 on the chemical processes by which .NO is produced from the precursors, rather than to an increased sensitivity of the hypoxic cells towards .NO.

SUBMITTER: Ioannidis I

PROVIDER: S-EPMC1217688 | biostudies-other | 1996 Sep

REPOSITORIES: biostudies-other

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Project description:The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-D-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC-MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer-crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4-4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.

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Enhanced release of nitric oxide causes increased cytotoxicity of S-nitroso-N-acetyl-DL-penicillamine and sodium nitroprusside under hypoxic conditions.

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