Michel Feletou

..Whether this will be the long awaited therapy based on manipulation of NPY receptors will await further studies of long term efficacy and more importantly a favorable side effect profile...

..TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation...

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..Nevertheless, because EDCFs converge to activate TP receptors, selective antagonists of this receptor, by preventing endothelium-dependent contractions, curtail the endothelial dysfunction in diseases such as hypertension and diabetes...

..The discovery of specific inhibitors of the endothelial cell hyperpolarization allows the assessment of the contribution of EDHF-mediated responses in the control of vascular tone...

..Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets...

..Conversely, blockers of IK(Ca) may prevent restenosis and that of BK(Ca) channels sepsis-dependent hypotension...

..A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases...

..In aorta from WKY those responses are reduced by aging and, in SHR, are already compromised at 3 mo. This dysfunction of the IP receptor is only partially explained by a general dysfunction of the adenylate cyclase pathway...

..The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury...

..When the sGC is oxidized, BAY 58-2667 becomes a relevant anti-aggregating agent, which synergizes with the cAMP-dependent pathway...

..Thus, in the aorta of SHR, endothelium-dependent contractions elicited by ATP involve the release of thromboxane A(2) and prostacyclin with a possible contribution of PGH(2)...

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..Therapeutic interventions do not necessarily restore a proper endothelial function and, when they do, may improve only part of these variables...

..Among the diffusible endothelial factors nitric oxide (NO) plays a key role, particularly in large blood vessels. This chapter briefly reviews the interactions between NO and the other vasomotor signals released by the endothelial cells...

..Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI2 with a concomitant contribution of PGH2...

..The purpose of the present study was to determine whether a stimulator of soluble guanylyl cyclase, BAY 41-2272, inhibits platelet aggregation and to clarify its interaction with nitric oxide (NO)...

..These various mechanisms are not necessarily mutually exclusive and, depending on the vascular bed and the experimental conditions, can occur simultaneously or sequentially, or also may act synergistically...

..This brief review highlights these different endothelial pathways as potential drug targets for novel treatments in hypertension and the associated endothelial dysfunction and end-organ damage...

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..6. Thus, these results confirm that adipocytes are a target for circulating ET-1 and demonstrate that the activation of the ETA receptor subtype can prevent TNFalpha-induced iNOS expression...

..This channel is opened by activation of the EDHF pathway and likely mediates the charybdotoxin-sensitive component of the EDHF response...

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..Therefore, TP antagonists, because of this triple activity, may have a unique potential for the treatment of cardiovascular disorders...

..The possibility that long-term NPY Y2 agonism could cause bone thinning and retinal angiogenesis are of particular concern and will need to be investigated as drug discovery moves forward...

..Additionally, the endothelium can produce other factors such as lipoxygenases derivatives or hydrogen peroxide (H2O2). These different mechanisms are not necessarily exclusive and can occur simultaneously...

..Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes...

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..TP receptor antagonists represent a promising avenue for the prevention of vascular disease in part because of these pleiotropic actions that extend beyond their antithrombotic properties...