title: Monophosphoryl lipid A: a novel nitric oxide-mediated therapy to attenuate platelet thrombosis?
abstract: Nitric oxide (NO) is a potent inhibitor of platelet aggregation. However, the benefits of NO-based therapies can be confounded by concomitant hypotension. 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 were to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism but 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 coronary blood flow (CFVs) caused by the formation/dislodgement of platelet-rich thrombi. In protocol I, dogs received MLA (100 microg/kg + 40 microg/kg/h) or vehicle beginning 15 min before stenosis. Protocol II was identical, except the NOS inhibitor aminoguanidine was coadministered with MLA/vehicle. Coronary patency was assessed throughout the initial 3 h after injury + stenosis. 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 baseline flow, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treated versus vehicle-treated dogs. In contrast, in protocol II, vessel patency was comparable in both groups. Finally, whole blood impedance aggregometry (protocol HI) 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 and in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.
authors.affiliation: Heart Institute, Good Samaritan Hospital, and Department of Medicine, University of Southern California, Los Angeles 90017-2395, USA. karinp@dnamail.com
authors.forename: K
authors.initials: K
authors.lastname: Przyklenk
authors.forename: K
authors.initials: K
authors.lastname: Hata
authors.forename: P
authors.initials: P
authors.lastname: Whittaker
authors.forename: G T
authors.initials: GT
authors.lastname: Elliott
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000517:prevention & control*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006146:Guanidines / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*
chemical_list: D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D006146:Guanidines; D008050:Lipid A; D009569:Nitric Oxide; C048436:monophosphoryl lipid A; C004479:pimagedine