Inhibition of thrombosis by a novel platelet selective S-nitrosothiol compound without hemodynamic side effects.
Platelet and endothelial production of bioactive nitric oxide (NO) is known to be impaired in acute coronary syndromes, thus compounds that release NO are useful candidates to restore NO-vascular functions.


OBJECTIVE
We have studied whether donation of NO with a novel platelet-selective S-nitrosothiol compound (LA810) at a systemic level can inhibit thrombosis elicited by damaged vessel wall (eroded and disrupted vessel wall) at hemodynamic conditions typical of patent and stenotic coronary arteries.


METHODS
Thrombogenicity was measured in the porcine experimental model and assessed as platelet-thrombus formation in the ex vivo Badimon perfusion chamber. After baseline perfusions, female pigs (Large WhitexLandrace) were given intravenous infusion of LA810 or GSNO standard S-nitrosothiol during 2 h. Changes in blood pressure, heart rate and in vitro platelet aggregation were measured.


RESULTS
LA810 significantly decreased thrombus formation at any degree of vascular damage and shear rate (p<0.001) without hypotensive side-effects or heart rate variations. In contrast, inhibition of thrombus formation by GSNO required high doses associated to hypotensive episodes. Platelet aggregation induced by collagen was inhibited after nitrosothiol infusion in whole blood (LA810) and platelet rich plasma (LA810 and GSNO). In addition, there was a drug-dependent rise in platelet guanosine 3',5'-cyclic monophosphate (cGMP) levels.


CONCLUSIONS
This new anti-ischemic NO-donor (NOd) LA810 that inhibits platelet function without hypotensive side-effects seems a highly efficacious strategy to reduce acute thrombosis triggered by coronary artery disease.
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB), Av S Antoni M Claret 167, 08025 Barcelona, Spain.
Gemma
G
Vilahur
María Isabel
MI
Baldellou
Estefania
E
Segalés
Eduardo
E
Salas
Lina
L
Badimon
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003327:Coronary Disease / Q000378:metabolism / Q000473:pathology; D003328:Coronary Thrombosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D023421:Models, Animal; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D009603:Nitroso Compounds / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D026403:S-Nitrosothiols / Q000627:therapeutic use; D013314:Stress, Mechanical; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D013552:Swine
C487623:N-(N-gamma-L-glutamyl-2-amino-2-(4-(4-S-nitrosomercapto-1-methylpiperidine)acetyl)glycine); D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; D006152:Cyclic GMP; D005998:Glycine