Summary
Nitric oxide (NO) regulates both vascular tone and platelet function. Since thrombotic
diseases and their animal models consist of both vascular and platelet components,
the functional mechanisms by which NO and endothelial nitric oxide synthase (eNOS)
regulate thrombotic events are unclear. Experiments were conducted by measuring collagen-induced
aggregation of freely circulating radio-labelled platelets in the pulmonary vasculature
of anaesthetised mice via external detection probes. In addition, cardiac haemodynamic function was assessed
by invasive catheterisation during thrombotic stimulation. Platelet aggregation responses
were shown to occur independently of changes in vessel tone induced by pharmacological
vasoconstriction or vasodilatation. Acute NOS inhibition significantly potentiated
the amplitude and duration of platelet aggregation and an NO donor had an inhibitory
effect. In contrast, in eNOS−/− mice, the amplitude of platelet aggregation was not affected although the response
was protracted following moderate thrombotic stimulation. Thrombosis induced changes
in haemodynamic performance were sensitive to vasomodulation and were potentiated
by both NOS inhibition and in eNOS−/− mice. In conclusion, endogenous NO and exogenously applied NO donors exert an antithrombotic
effect in vivo through a direct suppression of platelet aggregation. In contrast, eNOS exerts a
powerful antithrombotic effect upon the vascular components of thrombosis but has
a more subtle effect on the duration of thrombotic responses that are platelet-mediated.
Our data demonstrate the differential roles of eNOS and general NO bioavailability
in regulating vascular and platelet activity during thrombosis.
Keywords
Animal models - endothelium - nitric oxide - pharmacology - platelet
