EDHF: An update

The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term 'endothelium-derived hyperpolarizing factor' (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H 2O 2, CO, H 2S and various peptides can be released by endothelial cells. These factors activate different families of K + channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca 2+ concentration of the endothelial cells, followed by the opening of SK Ca and IK Ca channels (small and intermediate conductance Ca 2+-activated K + channels respectively). These channels have a distinct subcellular distribution: SK Ca are widely distributed over the plasma membrane, whereas IK Ca are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SK Ca activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IK Ca activation, K + efflux can activate smooth muscle Kir2.1 and/or Na +/ K +-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. 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. © The Authors Journal compilation © 2009 Biochemical Society.postprin

Vasoconstrictor prostanoids

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.postprin

Teaching TEI: The Need for TEI by Example

The Text Encoding Initiative (TEI)1 has provided a complex and comprehensive system of provisions for scholarly text encoding. Although a major focus of the ‘digital humanities’ domain, and despite much teaching effort by the TEI community, there is a lack of teaching materials available, which would encourage the adoption of the TEI's recommendations and the widespread use of its text encoding guidelines in the wider academic community. This article describes the background, plans, and aims of the TEI by Example project, and why we believe it is a necessary addition to the materials currently provided by the TEI itself. The teaching materials currently available are not suited to the needs of self directed learners, and the development of stand alone, online tutorials in the TEI are an essential addition to the extant resources, in order to encourage and facilitate the uptake of TEI by both individuals and institutions

Effects of probiotics in patients with diabetes mellitus type 2 : study protocol for a randomized, double-blind, placebo-controlled trial

Background: Low grade chronic inflammation is observed in patients with type 2 diabetes mellitus (T2DM). Endotoxin derived from gut bacteria may act as a potent inflammatory stimulant. Probiotics, which are believed to contain health promoting live microorganisms, may influence circulating endotoxin levels. Ingestion of live probiotic cultures may alter gut microbiota in a beneficial manner to reduce inflammation; no information is available whether or not they do so in patients with T2DM. Therefore, the aim of this study is to characterize the beneficial effects of probiotics on circulating endotoxin levels and other biomarkers related to systemic low-grade inflammation in patients with T2DM. Methods: One hundred and twenty consenting adult Saudi T2DM patients (naïve or newly diagnosed and without co-morbidities) will be enrolled in this clinical trial and randomized to receive daily placebo or probiotics (Ecologic®Barrier) for 26 weeks in a double-blind manner. Inflammatory and metabolic markers will be measured and fecal samples analyzed. Measurements/samples will be obtained at baseline and after 4, 8, 12/13 and 26 weeks of treatment. Discussion: It is expected that the probiotic product will induce beneficial changes in gut microbiota, reduce the systemic inflammatory state through altering systemic endotoxin levels and, as such, reduce the systemic inflammatory response observed in T2DM subjects. Trial registration: ClinicalTrials.gov Identifier: NCT0176551

Mechanisms responsible for coronary vasospasm

Studies have been conducted on isolated segments of the left circumflex coronary artery of the dog to gain information on the mechanism or mechanisms of vasospasm. Coronary arteries contain both postjunctional alpha1- and beta1-adrenoceptors, and both are accessible to norepinephrine released from the sympathetic nerves. However, owing to the dominance of the beta1-adrenoceptors, sympathetic stimulation causes relaxation of the vascular smooth muscle. In the primary branches of the circumflex artery, only beta1-adrenoceptors are present. In patients with spasm of the coronary arteries, blockade of the beta1-adrenoceptors may aggravate the spasm by permitting the unopposed constrictor action of the sympathetic nerves on the alpha1-adrenoceptors on these vessels.The blood platelets contain substances, including 5-hydroxytryptamine (serotonin) and thromboxane A2, which can cause constriction of vascular smooth muscle. These substances are released whenever platelets aggregate. The normal endothelium, by forming and releasing prostacyclin, inhibits platelet aggregation. In addition, in response to platelet products, the normal endothelium forms one or more inhibitory substances that cause relaxation of the underlying smooth muscle. Also, if any thrombin is formed, this also causes an endotheliummediated relaxation of the artery. Patients with coronary artery spasm usually have morphologic changes in the artery at the site of the spasm. Thus, platelets can aggregate at the site and the resultant release of serotonin and thromboxane A2, acting directly on the smooth muscle, causes constriction of the artery. Hypoxia of the myocardium follows and this augments the constriction

Endothelin XIII

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Endothelium-derived Vasoactive Factors and Hypertension: Possible Roles in Pathogenesis and as Treatment Targets

Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally, another pathway associated with the hyperpolarization of the underlying smooth muscle cells plays a predominant role in resistance arteries. Endothelial dysfunction is a multifaceted disorder, which has been associated with hypertension of diverse etiologies, involving not only alterations of the L-arginine NO-synthase–soluble guanylyl cyclase pathway but also reduced endothelium-dependent hyperpolarizations and enhanced production of contracting factors, particularly vasoconstrictor prostanoids. 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

Liquid Chromatography Electron Capture Dissociation Tandem Mass Spectrometry (LC-ECD-MS/MS) versus Liquid Chromatography Collision-induced Dissociation Tandem Mass Spectrometry (LC-CID-MS/MS) for the Identification of Proteins

Electron capture dissociation (ECD) offers many advantages over the more traditional fragmentation techniques for the analysis of peptides and proteins, although the question remains: How suitable is ECD for incorporation within proteomic strategies for the identification of proteins? Here, we compare LC-ECD-MS/MS and LC-CID-MS/MS as techniques for the identification of proteins.Experiments were performed on a hybrid linear ion trap–Fourier transform ion cyclotron resonance mass spectrometer. Replicate analyses of a six-protein (bovine serum albumin, apo-transferrin,lysozyme, cytochrome c, alcohol dehydrogenase, and β-galactosidase) tryptic digest were performed and the results analyzed on the basis of overall protein sequence coverage and sequence tag lengths within individual peptides. The results show that although protein coverage was lower for LC-ECDMS/MS than for LC-CID-MS/MS, LC-ECD-MS/MS resulted in longer peptide sequence tags,providing greater confidence in protein assignment