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Platelets: intracellular signalling and cellular interaction
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Activation of platelets is essential to prevent excessive blood loss at the site of vascular injury. These highly reactive cell fragments are also involved in several pathological conditions, in particular arterial thrombosis, which, in the coronary vessels, can lead to reduced blood flow, vessel occlusion and myocardial infarction.

The present research was focused on the anti-platelet properties, mechanisms of actions, and interactions of GEA 3175 and adenosine. The former a novel nitric oxidecontaining and cyclic GMP-elevating compound, the latter a cyclic AMP-elevating · purine nucleoside. Separately, the two substances significantly reduced the cytosolic , Ca2+ responses, but only marginally suppressed subsequent functional responses in thrombin-stimulated human platelets. However, coadministration of the compounds synergistically inhibited platelet aggregation and abolished dense granule secretion 1 and exposure of P-selectin, and also markedly reduced binding of fibrinogen to the i surface of platelets. The results imply that the stronger inhibition of platelet functions was due to potent blocking of the initial Ca2+ transient and abrogation of mechanisms involved in the influx of extracellular Ca2+. Together, the findings clearly manifest the importance of an interaction between different inhibitory intracellular pathways in order to completely suppress the activity of tbrombin activated platelets.

Cell- and drug-comparative studies revealed that GEA 3175 provoked aremarkable long-acting inhibition of contractile responses and a concomitant i sustained increase in cyclic GMP levels in airway smooth muscle tissue. The mechanisms of relaxation involved iberiotoxin-sensitive K + channels and okadaic ' acid-sensitive phosphatases. Separately, GEA 3175 and adenosine markedly inhibited the respiratory burst in chemoattractant-activated neutrophil granulocytes. Opposite to the situation in platelets, the two compounds did not interact synergistically and coadministration had only a negligible effect on cytosolic Ca2+ signals in neutrophils. These data clearly demonstrate cell type-specific responses to cyclic GMP- and cyclic AMP-elevating agents.

This thesis also delineates the regulatory effects of platelets on neutrophil cellular and intracellular responses. Simple mixture of suspensions of human platelets and neutrophils caused prominent changes in the neutrophil in regard to cytoskeletal arrangement, cytosolic Ca2+ responsiveness, and capacity to generate reactive oxygen species. Platelet-derived factor(s) induced a marked suppression of the respiratory burst in activated neutrophils, an effect attributed to peripheral accumulation of ! filamentous actin and enhanced release of endogenous adenosine from the neutrophil. The chemotactic-peptide-induced rise in cytosolic Ca2+ in neutrophils was dramatically amplified in the presence of platelets, and ATP released from the platelets may play a role in this priming phenomenon, However, additional experiments showed that the amplified Ca2+ response was virtually independent of the state of activation of the platelet, required extracellular Ca2+ ions, and was completely insensitive to the NO-donor GEA 3175. Further analysis strongly indicated that platelets affected the cyclic AMP-sensitive phase of the Ca2+ response in neutrophils. In conclusion, multiple mediators and mechanisms participate in the platelet-mediated modulation of neutrophil responses, and greater understanding of the complex mechanisms and consequences of the interactions between these blood cells may provide useful information for the design of pharmacological tools and methods to control the inflammatory reaction.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1998. , 92 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 569
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-27485Local ID: 12139ISBN: 91-7219-055-8OAI: diva2:248037
Public defence
1998-10-09, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)

Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.

Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-11-09Bibliographically approved

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