A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters

Abstract

Platelets are involved in the clinical presentations of ischemic heart disease. Our objective was to study the antithrombotic effects of a new nitric oxide donor (LA419), a neutral sugar organic nitrate with a protected thiol group in its molecular structure. Animals were randomly distributed in three groups: I) oral administration of LA419 (0.9-1.8-3.6-5 mg/kg/d, 10 days); II) oral administration of standard IS-5-MN (0.9-1.8 mg/kg/d, 10 days); III) non-treated group (control). In catheterized pigs, thrombosis was studied under controlled rheological conditions by radioisotopic evaluation of deposited platelets on damaged vessel wall, placed in an extracorporeal perfusion chamber. Changes in blood pressure, heart rate, and platelet aggregation were evaluated. Results have shown that LA419 significantly decreased thrombus formation according to the degree of vascular damage, and shear rate conditions in a dose-dependent manner (p<0.005), without significant modifications on blood pressure and/or elevation of liver enzymes. In contrast, IS-5-MN only showed a significant reduction on platelet deposition at the high dose, that was associated to hypotension and elevation of liver enzymes. Therefore, we conclude that this new anti-ischemic NO-donor (NOd) LA419 that inhibits platelet function without modifying blood pressure may be a highly efficacious strategy to passivate platelet activation induced by a damaged vessel wall.

LA419, a Novel Nitric Oxide Donor, Prevents Pathological Cardiac Remodeling in Pressure-Overloaded Rats Via Endothelial Nitric Oxide Synthase Pathway Regulation

“…Interestingly, LA419 was not able to modify the cardiac cGMP levels at basal condition. These results, together with the previous observation that LA419 infusion did not increase cGMP plasma levels, 12 support the idea that bioactive NO released by LA419 was not high enough to activate soluble guanylate cyclase. Therefore, the normal tissular cGMP could be re-established as a consequence of restored normal eNOS expression in stenosed rats treated with LA419 and not as a consequence of the direct LA419 effect on soluble guanylate cyclase.…”

“…LA419 is a new neutral sugar organic nitrate with a protected thiol group in its molecular structure that, at therapeutic doses, has no effect on systemic blood pressure and has important antithrombotic 10,11 and anti-ischemic properties, exceeding those observed with the standard NO donor isosorbide-5-mononitrate. 12 Based on this evidence, the present study was designed to evaluate the effect of chronic treatment with the novel NO donor LA419 on cardiac remodeling associated with cardiac hypertrophy development in rats subjected to Received May 8, 2007; first decision May 29, 2007; revision accepted October 12, 2007 …”

“…LA419 is a new neutral sugar organic nitrate with a protected thiol group in its molecular structure that, at therapeutic doses, has no effect on systemic blood pressure and has important antithrombotic 10,11 and anti-ischemic properties, exceeding those observed with the standard NO donor isosorbide-5-mononitrate. 12 Based on this evidence, the present study was designed to evaluate the effect of chronic treatment with the novel NO donor LA419 on cardiac remodeling associated with cardiac hypertrophy development in rats subjected to aortic stenosis and to investigate its effect on the endogenous NO pathways with special attention to the constitutive NO synthases, endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) isoforms, and the allosteric regulators, the chaperone heat shock protein 90 (Hsp90) and caveolin-3.…”

Proteomic Signature of Thrombin-Activated Platelets After In Vivo Nitric Oxide–Donor Treatment

“…14 This treatment regime inhibits platelet aggregation induced by high doses of potent agonists, such as collagen and ADP, and platelet deposition on damaged vessel wall under controlled flow conditions. 14 All procedures were in accordance with National Institutes of Health guidelines and followed the American Physiological Society Guidelines for animal research.…”

“…We showed antithrombotic properties that exceeded those of IS-5-MN (a standard mononitrate) and reported that LA419 increased platelet cGMP levels. 14,15 By means of a proteomic approach, here we aimed at expanding our understanding into the molecular mechanisms by which NO exerts its antiplatelet effects. As platelets are anucleated, activation is mainly controlled by translocation of proteins, altered interactions, and posttranslational modifications, such as phosphorylation and glycosylation.…”