LOCALIZING ANTITHROMBOTIC AND VASODILATORY ACTIVITY WITH A NOVEL, ULTRAFAST NITRIC-OXIDE DONOR

Reaction of nitric oxide (NO) with L-proline in methanolic sodium meth oxide yields a diazeniumdiolate product, C5H7N3O4Na2 . CH3OH (PROLI/NO ), that can be stabilized in basic solution but that dissociates to pr oline (1 mol) and NO (2 mol) with a half-life of only 1.8 s at pH 7.4 and 37 degrees C. This kinetic behavior has allowed the generation of highly localized antiplatelet and vasodilatory effects. By infusing so lutions containing 4 mu M PROLI/NO in 0.1 M sodium hydroxide at the ra te of 1 nmol . min(-1) immediately upstream from a polyester vascular graft in the unheparinized baboon circulatory system, for example, pla telet deposition at the normally thrombogenic graft surface was substa ntially reduced relative to controls receiving only 0.1 M sodium hydro xide. In a second study, infusion of PROLI/NO into the right atrium of sheep with induced pulmonary hypertension selectively dilated the lun g vasculature, dose-dependently reducing the pulmonary arterial pressu re by as much as 9 mmHg with no observable effect on the systemic arte rial pressure at an infusion rate of up to 24 nmol . kg(-1). min(-1). PROLI/NO could also be formulated as an insoluble polymer blend that r eleased NO smoothly for prolonged periods. The results suggest that lo calized delivery of diazeniumdiolates such as PROLI/NO which generate NO with extreme rapidity on entering the blood stream may hold conside rable promise for inhibition of thrombus formation, selective dilation of the vasculature, and other research and clinical applications.