WILLIAM BRYSON CAMPBELL

..This new EDHF classification provides a framework for understanding EDHF activity in physiological and pathological conditions...

..Additionally, this lipoxygenase pathway mediates the nonnitric oxide, nonprostaglandin relaxations to ACh in the rabbit aorta by acting as a source of an endothelium-derived hyperpolarizing factor...

..These findings indicate that epoxyeicosatrienoic acids act as endothelium-derived hyperpolarizing factors and regulate arterial tone...

..This article reviews the latest studies concerning the characterization of endothelium-derived hyperpolarizing factors, the mechanisms of factor release and alterations of the factors...

..Thus, the EETs are endothelium-derived hyperpolarizing factors mediating a portion of the relaxations to acetylcholine, bradykinin, shear stress, and cyclic stretch and regulate vascular tone in vitro and in vivo...

..14,15-DHET relaxes coronary arteries through activation of K(Ca) channels. Endothelial cells, but not smooth muscle cells, convert EETs to DHETs, and this conversion results in a loss of vasodilator activity...

..These studies indicate that 14(S),15(R)-EET is a sufficient endogenous activator of BK(Ca) channels in coronary SMCs...

..The present study indicates that conversion of 14,15-EE5ZE to 14,15-DHE5ZE produces a 14,15-EET-selective antagonist that will be a useful pharmacological tool to identify EET receptor(s) and EET function in the cardiovascular system...

..This provides a mechanism by which Ang II concurrently increases adrenal blood flow and steroidogenesis...

..Thus, adrenic acid metabolites could function as endogenous endothelium-derived and zona glomerulosa-derived hyperpolarizing factors in the adrenal cortex and contribute to the regulation of adrenal blood flow...

..14,15-EET-P(125)ISA is a new radiolabeled tool to study EET metabolism and binding. Our results also provide preliminary evidence that EETs exert their biological effect through a membrane binding site/receptor...

..The THFDs potently induced relaxation of pre-contracted bovine arteries...

..These studies indicate that EDSF enhances the steroidogenic effect of AII. In the adrenal gland, ECs are in close anatomical relationship with ZG cells and may sensitize ZG cells to the steroidogenic action of AII by releasing EDSF...

..This confirms the role of HEETA and THETA as endothelium-derived relaxing factors...

..Our results demonstrate that 15-LOX-2 expression is significantly reduced and this reduction may promote proliferation in human head and neck carcinoma. 15-LOX-2 may be a possible biomarker in human head and neck malignancy...

..Application of this methodology to the analysis of the liver endogenous EETs demonstrates stereospecific biosynthesis and corroborates the role of cytochrome P450 as the endogenous arachidonic acid epoxygenase...

..In addition, a component was unmasked following SK(Ca) and IK(Ca) blockade, attributable to activation of BK(Ca) channels by cytochrome P-450 metabolites...

..CYP450s and sEH may be endogenous sources of these compounds, and sEH inhibition has the potential to alter myocardial perfusion, depending on which EETs are produced endogenously...

..CONCLUSIONS: 15-LO-I is expressed in rabbit aortic endothelium and is important in endothelium-dependent regulation of vascular tone...

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..Therefore, inhibitors of 2-AG hydrolysis could potentially serve as therapeutic agents for the treatment of prostate cancer. (c) 2007 Wiley-Liss, Inc...

..We conclude that ZG cells release EETs and this release is stimulated by ACTH. Interaction of endocrine and vascular cells represents a mechanism for regulating adrenal blood flow and couples steroidogenesis to increased blood flow...

..These results suggest that FAAH regulates 2-AG hydrolysis and invasion of prostate carcinoma cells and is potentially involved in prostate tumorigenesis...

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..5 +/- 1.4%, and by BW755C to -18.8 +/- 3.5%. The present study indicates that the age-related decrease in ACh-induced hypotension is mediated by the decreased synthesis of the 15-LO-1 metabolites THETAs and HEETAs...

..These data also suggest that 14,15-EEZE is not blocking the mitochondrial ATP-sensitive potassium channel as a mechanism for antagonizing the cardioprotective effects of the EETs...

..It relaxes smooth muscle by activating K+ channels. The specific structural and stereochemical requirements for K+ channel activation suggest that a specific binding site or receptor of 11,12,15-THETA is involved in these actions...

..These results indicate that 15-H-11,12-EETA is produced by the aorta, hydrolyzed by sEH to 11,12,15-THETA, and mediates relaxations by membrane hyperpolarization. 15-H-11,12-EETA represents an endothelium-derived hyperpolarizing factor...

..Therefore, increased expression of 15-LO-1 increases acetylcholine relaxation in arteries and hypotensive responses in rabbits because of increased hydroxy-epoxyeicosatrienoic acid and trihydroxyeicosatrienoic acid synthesis...

..Production and metabolism of EETs as well as their specific cellular signaling mechanisms are discussed...

..These data indicate that aortic 15-LO-1 expression and activity are downregulated with aging in rabbits. This decrease is paralleled by the reduced synthesis of vasoactive THETA and HEETA and aortic relaxations to acetylcholine and AA...

..These findings suggest that an inhibitory interaction exists between 2 EDHFs in the human coronary microcirculation. CYP epoxygenases are directly inhibited by H2O2, and this interaction may modulate vascular EET bioavailability...

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..PGD2 appears to be important in regulating mucosal blood flow in patients with IBD, implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs...

..The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation...

..These results suggest that arachidonic acid induces endothelium-dependent hyperpolarization and relaxation of rabbit aorta through activation of smooth muscle, apamin-sensitive K+ currents...

..Further hydrolysis of the epoxy group of the HEETAs results in the formation of 11,12,15- and 11,14,15-THETAs. The HEETAs and THETAs are both vasodilators and may function as important regulators of vascular tone...

..8 nm. The detection of 12-lipoxygenase and cyclooxygenase-1 in single bovine coronary artery endothelial cells and the binding of angiotensin II to its receptors in zona glomerulosa cells was demonstrated...

..It also inhibits the EDHF component of bradykinin-induced, methacholine-induced, and arachidonic acid-induced relaxation. These results suggest that 14,15- or 5,6 -EET act as an EDHF in bovine coronary arteries...

..CONCLUSIONS: These data indicate that in the vascular endothelium, IL-13 induces the expression of 15-lipoxygenase and increases the production of the vasodilatory eicosanoids HEETA and THETA...

..6+/-1.3%). In conclusion, trioxilin C(3) acid was isolated and identified as a novel biologically active arachidonic acid metabolite formed by rabbit aorta when 12-lipoxygenase is supplied exogenously...

..Although a clear causal relationship remains to be demonstrated, these data suggest a previously unrecognized role for 15-LO in hypoxic vasoconstriction in neonatal mammals...

..These results suggest that the cADPR signaling pathway participates in the contraction of small coronary arterial smooth muscle and Ca(2+) release induced by activation of M(1) muscarinic receptors...

..We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca(2+)-activated K(+) channels (BK(Ca))...

..6-Keto-PGF(1alpha) was the major metabolite in these cells. The production of PGE(2) was threefold higher and PGD(2) was twofold higher in PC-3-S (invasive) cells than in PC-3-U (non-invasive) cells...

..These studies suggest that primary cultures of human umbilical vein endothelial cells contain adherent platelets that contribute to thromboxane synthesis...

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..Thus, a distinct molecular structure is required for EET activity, and alteration of this structure modifies agonist and antagonist activity. These findings support a role of EETs as EDHFs...

..In many vessels, they are an endothelium-derived hyperpolarizing factor (EDHF). However, it is unknown whether they act as an EDHF on platelets and whether this has functional consequences...

..The forceful contractile responses of these arterioles are consistent with their potential role in the regulation of adrenal blood flow...

..The data suggested that ACh activates PLC, DAG lipase, and MAG lipase pathway to release AA from membrane lipids. This pathway is important in regulating vasodilatory eicosanoid synthesis and vascular relaxation in rabbit aorta...

..These results demonstrate a new series of 2-AG hydrolysis inhibitors as a potential therapeutic approach for prostate cancer...

..These open endothelial IK(Ca) and SK(Ca) channels and also activate large-conductance calcium-sensitive K+ channels (BK(Ca)) on the surrounding myocytes...

..Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction...

..These results suggest that urinary free acids of 12-HETE and 20-HETE indicate an abnormality of the prostate gland...

..14,15-EEZE blocked the donor artery, endothelium-dependent, bradykinin-induced relaxations, and attenuated relaxations to 14,15-EET. These results suggest that EETs are transferable EDHFs in coronary arteries...

..PDPAs only activate large conductance calcium-activated K+ channels...

..The technique demonstrates the ability to determine the individual steroid in each enzymatic step of aldosterone synthesis and the activity of steroidogenic enzymes in adrenal ZG cells...

..2-AG is further hydrolyzed to AA, which is metabolized to vasoactive eicosanoids. These studies reveal a role for 2-AG in EC AA release and the regulation of coronary tone...

..production through activation of NAD(P)H oxidase. This ceramide-O2*-. signaling pathway may contribute importantly to endostatin-induced endothelial dysfunction...

..The full text of this article is available online at http://circres.ahajournals.org...

..Only 11(R),12(S),15(S)-THETA was comparable to natural material by HPLC, GC/MS, and in vitro bioassay...

..The acetylcholine-induced relaxation is largely mediated by an endothelium-dependent hyperpolarization mechanism, presumably through cytochrome P450 metabolites of arachidonic acid...

..These studies provide the first evidence that the ability of glibenclamide to inhibit TX-mediated contractions occurs independent of the vascular K(ATP) channel and is, instead, mediated by the blockade of the vascular TX receptor...

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..These studies will test the hypothesis that endogenous LO metabolites are important regulators of vascular tone and blood pressure in mice. ..

..We will determine if conferring cytochrome P450 epoxygenase activity on smooth muscle cells allows endogenously formed EETs to activate Kca channel activity and cause endothelium-independent relaxation. ..

..4) We will determine the role of endothelial NO in regulating steroidogenesis and adrenal blood flow in the in situ perfused adrenal gland and in vivo in anesthetized rats. ..

..We anticipate that successful completion of these studies will provide valuable insight into the role of the AEA/CB 1 signaling system in the brain. ..

..About 75-80% of instrument time will be available to these participants and the remaining time will be available to other investigators at the College. ..

..4. investigate the mechanism of smooth muscle dilation by 15-H-11,12-EETA and 11,12,15-THETA by determining their action on membrane potential and potassium channel activity. ..

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..These studies will provide specific pharmacological tools to study the role of EETs as EDHFs and provide new insights into the vascular action of the EETs. ..

..The regulation of adrenal vascular tone by ZG cells may have broader implications. This may represent a general pathway for regulation of vascular tone in many endocrine glands. ..

..These studies will provide specific pharmacological tools to study the role of EETs as EDHFs and provide new insights into the vascular action of the EETs. ..

..The regulation of adrenal vascular tone by ZG cells may have broader implications. This may represent a general pathway for regulation of vascular tone in many endocrine glands. ..

..We have coupled this technique with our ability to culture cells from the cerebellum as a unique approach to these goals. ..

..The regulation of adrenal vascular tone by ZG cells may have broader implications. This may represent a general pathway for regulation of vascular tone in many endocrine glands. ..

..In addition, we will develop several tools that will be valuable additions to the cannabinoid field in general, including a sensitive assay for AEA and a series of active and inactive analogs. ..

..Measurement of the metabolites, inhibitors of eicosanoid synthesis and K channels and infusions of the eicosanoids should provide insights into the contribution of the EETs to coronary microvascular tone. ..

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