Monophosphoryl lipid A: A novel nitric oxide-mediated therapy to attenuateplatelet thrombosis?

Nitric oxide (NO is a potent inhibitor of platelet aggregation. However, th e benefits of NO-based therapies can be confounded by concomitant hypotensi on. Monophosphoryl lipid A (MLA) is a nontoxic derivative of endotoxin that purportedly increases nitric oxide synthase (NOS) activity and, presumably , NO production. yet has a hemodynamically benign profile. Thus our aims we re to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism bu t without reductions in arterial pressure; and (b) the platelet inhibitory effects are manifest in vitro. To address the first aim, anesthetized dogs underwent coronary injury + stenosis, resulting in cyclic variations in cor onary blood flow (CFVs) caused by the formation/dislodgement of platelet-ri ch thrombi. In protocol I, dogs received MLA (100 mu g/kg + 40 mu g/kg/h) o r vehicle beginning 15 min before stenosis. Protocol II was identical, exce pt the NOS inhibitor aminoguanicidine was coadministered with MLA/vehicle. Coronary patency was as sessed throughout the initial 3 h after injury + st enosis. Infusion of MLA did not result in hypotension. However, in protocol I, the median nadir of the CFVs was higher (2.1 vs. 0.8 ml/min; p < 0.05), median duration of total thrombotic occlusion tended to be reduced (0 vs. 10.4 min; p = 0.1), and mean flow-time area, expressed as a percentage of b aseline now, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treat ed versus vehicle-treated clogs. In contrast, in protocol II, vessel patenc y was comparable in both groups. Finally, whole blood impedance aggregometr y (protocol III) revealed a significant reduction in the in vitro platelet aggregation in blood samples receiving exogenous MLA, which was blocked by coadministration of exogenous aminoguanidine, Thus MLA attenuates platelet- mediated thrombosis in both damaged and stenotic canine coronary arteries a nd in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.