Zhengrong Zhou

Effect of varying nitric oxide release to prevent platelet consumption and preserve platelet function in an in vivo model of extracorporeal circulation.

The gold standard for anticoagulation during extracorporeal circulation (ECC) remains systemic heparinization and the concomitant risk of bleeding in an already critically ill patient could lead to death. Normal endothelium is a unique surface that prevents thrombosis by the release of antiplatelet and antithrombin agents. Nitric oxide (NO) is one of the most potent, reversible antiplatelet agents released from the endothelium. Nitric oxide released from within a polymer matrix has been proven effective for preventing platelet activation and adhesion onto extracorporeal circuits. However, the critical NO release (NO flux) threshold for thrombus prevention during ECC has not yet been determined.1 Using a 4-hour arteriovenous (AV) rabbit model of ECC,2 we sought to find this threshold value for ECC circuits, using an improved NO-releasing coating (Norel-b ). Four groups of animals were tested at variable NO flux levels. Hourly blood samples were obtained for measurement of arterial blood gases, platelet counts, fibrinogen levels and platelet function (via aggregometry). A custom-built AV circuit was constructed with 36 cm of poly(vinyl)chloride (PVC) tubing, a 14 gauge (GA) angiocatheter for arterial access and a modified 10 French (Fr) thoracic catheter for venous access. The Norel-b coating reduced platelet activation and thrombus formation, and preserved platelet function — in all circuits that exhibited an NO flux of 13.65 × 10— 10 mol·cm—2·min—1. These results were significant when compared with the controls. With the Norel-b coating, the NO flux from the extracorporeal circuit surface can be precisely controlled by the composition of the polymer coating used, and such coatings are shown to prevent platelet consumption and thrombus formation while preserving platelet function in the animal. Perfusion (2007) 22, 193—200.

Metal ion-mediated nitric oxide generation from polyurethanes via covalently linked copper(II)-cyclen moieties

Polyurethanes are widely used in the manufacturing of biomedical catheters and other blood-contacting devices; however, thrombus formation still occurs, which renders these catheters ineffective unless systemic anticlotting agents are used. Nitric oxide (NO) is a well-known inhibitor of platelet activity. In the current study, two commercially available medical polyurethanes (Pellethane and Tecophilic) were derivatized to possess NO-generating Cu(II)-cyclen moieties pendant to the polymer backbone. A new three-step synthetic approach is used, that is simpler than a recently reported method to prepare Cu(II)-cyclen-polyurethane materials. Both derivatized polyurethanes were found to produce NO at levels at or above those of endothelial cells. A comparison between the modified commercial polyurethanes (hydrophobic vs. hydrophilic) is presented, including the synthetic scheme, extensive characterization, and coating application. These derivatized polymers may serve as useful coatings to prevent clotting on the surface of catheters and other blood-contacting biomedical devices.

1,1'-Dimethoxy-3,3'-dimethyl-3,3'-(hexane-1,6-diyl)bis(triazen-2-ium-2-olate): a nitric oxide donor.

The title compound, C10H24N6O4, is the most stable type of nitric oxide (NO) donor among the broad category of discrete N-diazeniumdiolates (NO adducts of nucleophilic small molecule amines). Sitting astride a crystallographic inversion center, the molecule contains a symmetric dimethylhexane-1,6-diamine structure bearing two planar O 2-methylated N-diazeniumdiolate functional groups [N(O)=NOMe]. These two groups are parallel to each other and have the potential to release four molecules of NO. The methylated diazeniumdiolate substituent removes the negative charge from the typical N(O)=NO− group, thereby increasing the stability of the diazeniumdiolate structure. The crystal was nonmerohedrally twinned by a 180° rotation about the real [101] axis. This is the first N-based bis-diazeniumdiolate compound with a flexible aliphatic main unit to have its structure analyzed and this work demonstrates the utility of stabilizing the N-diazeniumdiolate functional group by methylation.