Adrenoceptor α2A signalling countervails the taming effects of synchronous cyclic nucleotide-elevation on thrombin-induced human platelet activation and aggregation |
| |
| Institution: | 1. Brazilian Clinical Research Institute, São Paulo, Brazil;2. Duke Clinical Research Institute, Durham, NC;3. Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden;4. Department of Cardiology, University Hospitals Leuven, Leuven, Belgium;5. University of Alberta, Edmonton, AB, Canada;6. South Australian Health and Medical Research Institute, Flinders University and Medical Center, Adelaide, Australia;7. Green Lane Cardiovascular Service, Auckland, New Zealand;8. Gill Heart Institute and University of Kentucky, Lexington, KY;9. Bayer HealthCare Pharmaceuticals Inc, Whippany, NJ;10. Department of Medicine, Stanford University, Stanford, CA;11. Johnson & Johnson, New Brunswick, NJ;1. Department of Medicine, University of Verona, Verona, Italy;2. Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics – Division of Cardiac Surgery, University of Verona, Italy;1. Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada;2. Alberta Health Services, Alberta, Canada;3. Alberta Public Laboratory, Alberta, Canada;4. Provincial Laboratory for Public Health, Calgary, Alberta, Canada |
| |
| Abstract: | The healthy vascular endothelium constantly releases autacoids which cause an increase of intracellular cyclic nucleotides to tame platelets from inappropriate activation. Elevating cGMP and cAMP, in line with previous reports, cooperated in the inhibition of isolated human platelet intracellular calcium-mobilization, dense granules secretion, and aggregation provoked by thrombin. Further, platelet alpha granules secretion and, most relevant, integrin αIIaβ3 activation in response to thrombin are shown to be prominently affected by the combined elevation of cGMP and cAMP. Since stress-related sympathetic nervous activity is associated with an increase in thrombotic events, we investigated the impact of epinephrine in this setting. We found that the assessed signalling events and functional consequences were to various extents restored by epinephrine, resulting in full and sustained aggregation of isolated platelets. The restoring effects of epinephrine were abolished by either interfering with intracellular calcium-elevation or with PI3-K signalling. Finally, we show that in our experimental setting epinephrine likewise reconstitutes platelet aggregation in heparinized whole blood, which may indicate that this mechanism could also apply in vivo. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
