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Feletou M.,Institute Recherches Servier | Huang Y.,Chinese University of Hong Kong | Vanhoutte P.M.,University of Hong Kong | Vanhoutte P.M.,Chonbuk National University
Pflugers Archiv European Journal of Physiology | Year: 2010

In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endotheliumdependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation. © Springer-Verlag 2009.


Roger S.,Institute Recherches Servier | Paysant J.,Institute Recherches Servier | Badier-Commander C.,Institute Recherches Servier | Cordi A.,Institute Recherches Servier | And 2 more authors.
Vascular Pharmacology | Year: 2010

The purpose of the present study was to determine whether an activator of soluble guanylyl cyclase (sGC), BAY 58-2667, inhibits platelet aggregation and to clarify its mechanism of action. Blood was collected from anesthetized WKY rats. The aggregation of washed platelet was measured and the production of cAMP and cGMP was determined. BAY 58-2667 produced a partial inhibition of the ADP- and collagen-induced platelet aggregation, but did not significantly affect thrombin-induced aggregation. In ADP-induced platelet aggregation, the inhibitory effects of BAY 58-2667 were associated with an increased level of both cGMP and cAMP while that of the prostacyclin analogue, beraprost, was correlated only with an increase in cAMP. The inhibitor of sGC, ODQ, enhanced the effects of BAY 58-2667. The presence of l-nitroarginine, an inhibitor of NO-synthase, hydroxocobalamin, a scavenger of NO, or that of three different NO-donors did not affect the anti-aggregating effect of BAY 58-2667. However, the anti-aggregating effects of beraprost were potentiated by BAY 58-2667. Therefore, the platelet inhibitory effects of BAY 58-2667 are associated with the generation of cGMP and a secondary increase in cAMP, both being totally NO-independent. When the sGC is oxidized, BAY 58-2667 becomes a relevant anti-aggregating agent, which synergizes with the cAMP-dependent pathway. © 2010 Elsevier Inc.


PubMed | Institute Recherches Servier
Type: Journal Article | Journal: Pflugers Archiv : European journal of physiology | Year: 2010

In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endothelium-dependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation.


PubMed | Institute Recherches Servier
Type: Journal Article | Journal: Annals of medicine | Year: 2012

The present review first summarizes the complex chain of events, in endothelial and vascular smooth muscle cells, that leads to endothelium-dependent relaxations (vasodilatations) due to the generation of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) and how therapeutic interventions may improve the bioavailability of NO and thus prevent/cure endothelial dysfunction. Then, the role of other endothelium-derived mediators (endothelium-derived hyperpolarizing (EDHF) and contracting (EDCF) factors, endothelin-1) and signals (myoendothelial coupling) is summarized also, with special emphasis on their interaction(s) with the NO pathway, which make the latter not only a major mediator but also a key regulator of endothelium-dependent responses.


PubMed | Institute Recherches Servier
Type: Journal Article | Journal: British journal of pharmacology | Year: 2011

Endothelium-dependent contractions contribute to endothelial dysfunction in various animal models of aging, diabetes and cardiovascular diseases. In the spontaneously hypertensive rat, the archetypal model for endothelium-dependent contractions, the production of the endothelium-derived contractile factors (EDCF) involves an increase in endothelial intracellular calcium concentration, the production of reactive oxygen species, the predominant activation of cyclooxygenase-1 (COX-1) and to a lesser extent that of COX-2, the diffusion of EDCF towards the smooth muscle cells and the subsequent stimulation of their thromboxane A2-endoperoxide TP receptors. Endothelium-dependent contractions are also observed in various models of hypertension, aging and diabetes. They generally also involve the generation of COX-1- and/or COX-2-derived products and the activation of smooth muscle TP receptors. Depending on the model, thromboxane A(2), PGH(2), PGF(2), PGE(2) and paradoxically PGI(2) can all act as EDCFs. In human, the production of COX-derived EDCF is a characteristic of the aging and diseased blood vessels, with essential hypertension causing an earlier onset and an acceleration of this endothelial dysfunction. As it has been observed in animal models, COX-1, COX-2 or both isoforms can contribute to these endothelial dysfunctions. Since in most cases, the activation of TP receptors is the common downstream effector, selective antagonists of this receptor should curtail endothelial dysfunction and be of therapeutic interest in the treatment of cardiovascular disorders.

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