Local Delivery of an Ultra-short-acting Nitric Oxide- releasing Compound, DMHD/NO, Is Highly Effective in Inhibiting Acute Platelet-Thrombus Formation on Injured Arterial Strips

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Abstract
Background: Nitric oxide (NO) plays an important role in modulating platelet-vessel wall interaction following vascular injury. We examined the effects of local infusion of an ultra- short-acting NO-releasing compound: NO adduct of N, N'-dimethylhexanediamine (DMHD/NO), sodium nitroprusside, intravenous nitroglycerin, and aspirin on acute platelet-thrombus formation under conditions of high-shear blood flow in a rabbit extracor poreal perfusion model. Materials and Methods: Strips of porcine aortic media were perfused in a Badimon cham ber with arterial blood from 20 New Zealand White rabbits for 10 minutes at a shear rate of 1700 s-1. Thrombus formation was quantified by morphometric analysis of thrombus area. Effects on collagen-induced platelet aggregation, blood pressure, bleeding time, and acti vated clotting time were also examined. Results: DMHD/NO inhibited thrombus area and platelet aggregation in a dose-dependent manner with a 90% reduction in thrombus area (0.018 ± 0.039 vs 0.215 ± 0.085 mm 2/mm control, P < .001) and a 50% reduction in platelet aggregation (4.8 ± 4.4 vs 9.9 ± 4.1 Ω con trol, P = .04) at the highest dose of 1.0 nM/kg and 100 μM/L, respectively, without any effects on blood pressure, bleeding time, or activated clotting time. In contrast, equimolar concentrations of sodium nitroprusside and intravenous nitroglycerin had significantly reduced effects on thrombus area compared to DMHD/NO and were associated with signifi cant reductions in blood pressure and prolongation of bleeding time. Aspirin had no effect on thrombus area at 1 μM/kg but reduced thrombus area and prolonged bleeding time at 2 and 5 μM/kg. Conclusions: Local delivery of DMHD/NO produced a 90% inhibition of experimental acute platelet-thrombosis under high-shear flow conditions without producing adverse systemic hemodynamic or hemostatic effects. Thus, inhibition of thrombus formation by local delivery of a rapidly acting NO donor may be an effective strategy for prevention of arterial injury- induced thrombosis.