Distinct role and location of the endothelial isoform of nitric oxide synthase in regulating platelet aggregation in males and females in vivo.
The role of endogenous nitric oxide in regulating platelet function in vivo is incompletely understood. The enzymic and anatomic sources of bioactive NO remain unclear and the consequences of the differences in endothelial function between males and females to platelet responsiveness are not known. We employed a mouse model of platelet thromboembolism to assess platelet aggregation in vivo along with supporting in vitro studies to investigate these issues. Pharmacological nitric oxide synthase (NOS) inhibition protracted the duration of thromboembolic responses to ADP (adenosine diphosphate) and enhanced in vivo platelet aggregation following activation of the coagulation cascade. Collagen induced in vivo platelet aggregation was enhanced in female eNOS(-/-) mice and the NOS inhibitor L-NAME (Nω-Nitro-l-arginine methyl ester hydrochloride) potentiated collagen induced thromboembolism although selective iNOS and nNOS antagonists had no effect. None of the NOS inhibitors tested had significant effects on platelet aggregation in isolated whole blood. In conclusion, endogenous NO derived from eNOS in the vascular endothelium is a critical regulator of platelet function in vivo in both males and females with negligible roles of iNOS and nNOS. Despite the expression of NOS enzymes in circulating blood elements, there is no evidence of a functional role of endogenous NO from these cells in regulating platelets. eNOS and its up- and down-stream mediators are therefore potential anti-thrombotic targets.
National Heart and Lung Institute, Imperial College, London, UK.
Christopher
C
Moore
David
D
Sanz-Rosa
Michael
M
Emerson
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D021381:Protein Transport
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III