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Anthony P.c. Yim - One of the best experts on this subject based on the ideXlab platform.
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arrest in a porcine model cardioplegic Endothelium-Derived Hyperpolarizing Factor in coronary arteries during Protective effect of magnesium on the endothelial function mediated by
2013Co-Authors: Qin Yang, Wei Zou, Yao-chung Liu, Anthony P.c. YimAbstract:J Thorac Cardiovasc Surg 2002;124:361-370 Qin Yang, Yao-Chung Liu, Wei Zou, Anthony P. C. Yim and Guo-Wei He arrest in a porcine model Endothelium-Derived Hyperpolarizing Factor in coronary arteries during cardioplegicProtective effect of magnesium on the endothelial function mediated byhttp://jtcs.ctsnetjournals.org/cgi/content/full/124/2/361 on the World Wide Web at: The online version of this article, along with updated information and services, is located
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The significance of Endothelium-Derived Hyperpolarizing Factor in the human circulation.
Current vascular pharmacology, 2007Co-Authors: Qin Yang, Anthony P.c. YimAbstract:Although nitric oxide (NO) is recognized as the primary vasodilator derived from vascular endothelium in regulating the vascular tone, another Factor, i.e. the Endothelium-Derived Hyperpolarizing Factor (EDHF), has recently gained much attention and has been demonstrated to participate in vasodilatation in various blood vessels from different species, despite its unidentified nature. Most of the studies were conducted in animals and the knowledge of this Factor in the human vasculature is relatively limited. This review attempts to address the relevance of EDHF-mediated function in humans with the possible identity of EDHF and mechanisms involved. We consider the human vasculature where EDHF involvement has been documented including the systemic, coronary, and visceral (gastrointestinal, renal and reproductive) circulation. In these vascular systems, EDHF plays a role under physiological conditions either as another mechanism or as the “back-up” for NO. Furthermore, the contribution of EDHF changes under certain physiological conditions, such as ageing and pregnancy. In addition, altered EDHF function has been suggested in various pathological conditions including heart diseases, atherosclerosis, hypertension, diabetes, eclampsia, glaucoma, chronic renal failure, erectile dysfunction and ischemia-reperfusion period during open heart surgery. Pharmacological agents such as potassium channel openers or cytochrome P450 metabolites have been used to either protect or recover EDHF-dependent mechanisms. To further develop new therapeutic strategies that target EDHF, a better understanding is essential with regard to the function of EDHF under pathophysiological conditions in humans. Furthermore, the interaction between NO and EDHF as well as their relative contributions in various conditions are critical.
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Hypoxia-Reoxygenation, St. Thomas Cardioplegic Solution, and Nicorandil on Endothelium-Derived Hyperpolarizing Factor in Coronary Microarteries
The Annals of thoracic surgery, 2005Co-Authors: Ying-ying Dong, Anthony P.c. YimAbstract:Background We investigated effects of hypoxia-reoxygenation (H-R) with and without St. Thomas solution under clinically relevant temperatures and effects of nicorandil on Endothelium-Derived Hyperpolarizing Factor (EDHF)–mediated relaxation in porcine coronary microarteries. Methods In a myograph, rings of porcine microarteries (diameter 200 to 450 μm) were subjected to hypoxia (PO 2 Results The maximal EDHF-mediated relaxation was reduced after hypoxia for 30 minutes (59.9%% ± 1.6% versus 81.2%% ± 3.5%, p p p p p p p p p Conclusions We conclude that (1) H-R impairs EDHF-mediated relaxation in the coronary microarteries with more injury during prolonged H-R, and this can be partially eliminated by St. Thomas at 4°C but not at 37°C; and (2) as an additive, nicorandil may fully restore EDHF-mediated endothelial function after prolonged H-R.
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Electrophysiologic and mechanical evidence of superiority of Hyperpolarizing versus depolarizing cardioplegia in protection of Endothelium-Derived Hyperpolarizing Factor-mediated endothelial function: a study in coronary resistance arteries.
The Journal of thoracic and cardiovascular surgery, 2004Co-Authors: Anthony P.c. Yim, Qin Yang, Rong Zheng ZhangAbstract:Abstract Objective The advantages of Hyperpolarizing cardioplegia with potassium-channel openers versus depolarizing cardioplegia have been suggested but not demonstrated in coronary microarteries. This study examined the simultaneous electric and tonic alteration of coronary microarteries at the cellular level during and after exposure to depolarizing cardioplegia or Hyperpolarizing cardioplegia, with emphasis on Endothelium-Derived Hyperpolarizing Factor–mediated relaxation and hyperpolarization. Methods Porcine coronary microarteries (diameter, approximately 200-400 μm) were incubated with depolarizing cardioplegia (20 mmol/L KCl) or Hyperpolarizing cardioplegia (10 μmol/L aprikalim) for 1 hour. Cellular membrane potential with a glass microelectrode in a coronary smooth muscle cell and isometric force of the muscle were simultaneously measured in a myograph. Results Depolarizing cardioplegia incubation produced a stable contraction (from 4.9 ± 0.3 mN to 7.3 ± 0.4 mN) and depolarization (from −51 ± 1 mV to −41 ± 2 mV). In contrast, Hyperpolarizing cardioplegia relaxed (from 4.8 ± 0.3 mN to 3.5 ± 0.3 mN) and hyperpolarized (from −51 ± 2 mV to −56 ± 1 mV) the smooth muscle. After exposure to depolarizing cardioplegia, the bradykinin-induced, Endothelium-Derived Hyperpolarizing Factor–mediated relaxation reduced from 66.2% ± 5.0% to 18.4% ± 3.7% ( P P G -nitro-l-arginine. In contrast, Hyperpolarizing cardioplegia did not affect the bradykinin-induced responses. Conclusions In the coronary microarteries, exposure to Hyperpolarizing cardioplegia preserves whereas depolarizing cardioplegia reduces the Endothelium-Derived Hyperpolarizing Factor–mediated electric (hyperpolarization) and mechanical (relaxation) responses. Thus Hyperpolarizing cardioplegia is superior to depolarizing cardioplegia in protecting the endothelial function in the coronary microcirculation.
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Impaired Endothelium-Derived Hyperpolarizing Factor-mediated relaxation in porcine pulmonary microarteries after cold storage with Euro-Collins and University of Wisconsin solutions.
The Journal of thoracic and cardiovascular surgery, 2003Co-Authors: Wei Zou, Qin Yang, Anthony P.c. YimAbstract:Abstract Background Endothelium plays an important role in mediating the function of transplanted organs. The widely used University of Wisconsin solution impairs the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation in coronary arteries, but little is known about effects of lung preservation on Endothelium-Derived Hyperpolarizing Factor–mediated endothelial function. This study examined the effect of organ preservation solutions on the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation in the pulmonary microarteries (diameter 200 to 450 μm). Methods Two segments (1 as control) from the same microartery were allocated in 2 chambers of a myograph. After incubation with hyperkalemia (potassium 115 mmol/L), University of Wisconsin, or Euro-Collins solution (at 4°C for 4 hours), the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation was induced by bradykinin (−10 to −6.5 log M, n=8) or calcium ionophore (A 23187 , −9 to −5.5 log M, n=7) in U 46619 (−7.5 log M) precontracted rings in the presence of indomethacin (7 μmol/L), N G -nitro-l-arginine (300 μmol/L), and oxyhemoglobin (20 μmol/L). Results Exposure to hyperkalemia and storage with Euro-Collins or University of Wisconsin solution significantly decreased the relaxation to bradykinin (51.9 ± 8.4% vs 60.3 ± 6.1%, P = .02 or 49.3 ± 7.3% vs 65.2 ± 3.5%, P = .04) or A 23187 (12.5 ± 0.02% vs 33.8 ± 0.07%, P = .02 or 13.2 ± 0.03% vs 31.0 ± 0.05%, P = .03%). Conclusions Endothelium-Derived Hyperpolarizing Factor plays an important role in porcine pulmonary microarteries, and the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation is impaired when the lung is preserved with University of Wisconsin or Euro-Collins solution. This impairment may affect the lung function during the reperfusion period after lung transplantation.
Paul M Vanhoutte - One of the best experts on this subject based on the ideXlab platform.
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endothelium derived Hyperpolarizing Factor where are we now
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Michel Félétou, Paul M VanhoutteAbstract:The endothelium controls vascular tone not only by releasing nitric oxide (NO) and prostacyclin but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the denomination Endothelium-Derived Hyperpolarizing Factor (EDHF). We know now that this acronym includes different mechanisms. In general, EDHF-mediated responses involve an increase in the intracellular calcium concentration, the opening of calcium-activated potassium channels of small and intermediate conductance and the hyperpolarization of the endothelial cells. This results in an endothelium-dependent hyperpolarization of the smooth muscle cells, which can be evoked by direct electrical coupling through myo-endothelial junctions and/or the accumulation of potassium ions in the intercellular space. Potassium ions hyperpolarize the smooth muscle cells by activating inward rectifying potassium channels and/or Na + /K + -ATPase. In some blood vessels, including large and small coronary arteries, the endothelium releases arachidonic acid metabolites derived from cytochrome P450 monooxygenases. The epoxyeicosatrienoic acids (EET) generated are not only intracellular messengers but also can diffuse and hyperpolarize the smooth muscle cells by activating large conductance calcium-activated potassium channels. Additionally, the endothelium can produce other Factors such as lipoxygenases derivatives or hydrogen peroxide (H 2 O 2 ). These different mechanisms are not necessarily exclusive and can occur simultaneously.
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The impaired renal vasodilator response attributed to Endothelium-Derived Hyperpolarizing Factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate.
Diabetologia, 2000Co-Authors: A. S. De Vriese, Paul M Vanhoutte, J. Van De Voorde, Henk J. Blom, Marleen Verbeke, Norbert LameireAbstract:Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing Factors (nitric oxide, prostacyclin and an unidentified Endothelium-Derived Hyperpolarizing Factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor l-NG-nitroarginine methylester HCI (l-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. Results. The l-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired Endothelium-Derived Hyperpolarizing Factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of Endothelium-Derived Hyperpolarizing Factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-Derived Hyperpolarizing Factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes. [Diabetologia (2000) 43: 1116–1125]
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Bioassay of Endothelium-Derived Hyperpolarizing Factor
Biochemical and biophysical research communications, 1996Co-Authors: Jean-vivien Mombouli, Ibrahim Bissiriou, Valère D. Agboton, Paul M VanhoutteAbstract:Abstract Endothelium-Derived Hyperpolarizing Factor (EDHF) mediates vasodilatation in certain blood vessels, together with prostacyclin and NO. However, its chemical nature is not known. A perfusion-superfusion cascade was developed to confirm the diffusible nature of EDHF. Canine carotid arteries with endothelium were used as donors of vasoactive substances, whereas rings of coronary artery without endothelium were used as detectors. Inhibitors of NO synthesis and cyclooxygenase were present throughout, to avoid interference from NO and prostanoids. Measurements of membrane potential and isometric tension, in coronary arteries without endothelium (used as detectors), demonstrated the release of EDHF from the carotid arteries, following treatment with 8-methoxypsoralen, bradykinin and thimerosal. The K+-channel blocker tetraethylammonium inhibited the action of EDHF in the detectors. Thus, these results demonstrate that endothelial cells release a diffusible activator of K+-channels in vascular smooth muscle.
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Endothelium-Derived Hyperpolarizing Factor.
Clinical and experimental pharmacology & physiology, 1996Co-Authors: Michel Félétou, Paul M VanhoutteAbstract:1. Not all endothelium-dependent relaxations can be fully explained by the release of either nitric oxide (NO) and/or prostacyclin. Another unidentified substance(s) that hyperpolarizes the underlying vascular smooth muscle cells (Endothelium-Derived Hyperpolarizing Factor; EDHF) contributes to endothelium-dependent relaxations. 2. In blood vessels from various species these hyperpolarizations are resistant to inhibitors of NO synthase (NOS) and cyclo-oxygenase. In canine, porcine and human blood vessels the hyperpolarization cannot be mimicked by nitrovasodilators or exogeneous NO. However, in other species (rat, guinea-pig, rabbit) endothelium-dependent hyperpolarizations resistant to inhibitors of NOS and cyclo-oxygenase and hyperpolarizations to Endothelium-Derived or exogeneous NO can be observed in the same vascular smooth muscle cells. 3. In blood vessels where NO causes hyperpolarization, the response is blocked by glibenclamide, suggesting the involvement of ATP-dependent potassium channels. Hyperpolarizations caused by EDHF are insensitive to glibenclamide but, depending on the tissue, are inhibited by relatively small concentrations of tetraethylammonium (TEA) or by apamin or the combination of charybdotoxin plus apamin, indicating that calcium-dependent potassium channels are likely to be involved. 4. Metabolites of arachidonic acid, through the cytochrome P450 mono-oxygenase pathway (epoxyeicosatrienoic acids), are produced by the endothelial cells, increase the open-state probability of calcium-activated potassium channels sensitive to TEA or charybdotoxin, and induce the hyperpolarization of arterial smooth muscle cells, indicating that epoxyeicosatrienoic acids could be EDHF. However, in blood vessels from various species, cytochrome P450 inhibitors do not affect endothelium-dependent hyperpolarizations, indicating that EDHF is not yet identified with certainty. 5. Endothelium-Derived Hyperpolarizing Factor released from cultured endothelial cells reduces the intracellular calcium concentration in vascular smooth muscle cells and the EDHF component of the relaxation is proportionally more important in smaller than larger arteries. In aging animals and in various models of diseases, endothelium-dependent hyperpolarizations are diminished. 6. The identification of EDHF and/or the discovery of specific inhibitors of its synthesis and its action may allow a better understanding of its physiological and pathophysiological role(s).
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Endothelium-Derived Hyperpolarizing Factor: A key mediator of the vasodilator action of bradykinin
Immunopharmacology, 1996Co-Authors: Jean-vivien Mombouli, Ibrahim Bissiriou, Valère D. Agboton, Paul M VanhoutteAbstract:Bradykinin causes vasodilatation by stimulating the production of vasodilator prostanoids and nitric oxide (NO). However, there is an additional component that is mediated by a diffusible Endothelium-Derived Hyperpolarizing Factor (EDHF). The non-selective inhibitor of arachidonic acid metabolism eicosatetraynoic acid inhibits the EDHF-mediated component of the relaxation to bradykinin. Therefore, EDHF may be an archidonic acid metabolite. The diffusible nature of EDHF has been disputed because of the inability to consistently detect the Factor using perfusion bioassay techniques. However, administration of the acyltransferase inhibitor thimerosal facilitates the release of EDHF by endothelial cells in culture. Further studies are warranted to identify EDHF and explore further its functions in vasomotion.
Marianne Tare - One of the best experts on this subject based on the ideXlab platform.
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C-type natriuretic peptide: a new Endothelium-Derived Hyperpolarizing Factor?
Trends in pharmacological sciences, 2007Co-Authors: Shaun L. Sandow, Marianne TareAbstract:Vascular relaxation mediated by Endothelium-Derived Hyperpolarizing Factor (EDHF) is important for resistance artery function and is underpinned by hyperpolarization of the smooth muscle cells of the blood vessel wall. Debate surrounds the identity of EDHF and its mechanism of action, with the consensus being that there is no universal EDHF. Regional differences in vascular function reflect the complex mechanisms of EDHF. Two primary mechanistic pathways are implicated: (i) myoendothelial gap junctions mediating the spread of endothelial cell hyperpolarization or small signaling molecules (or both) to the smooth muscle; and (ii) diffusible mediators released from the endothelium, including K+ and epoxyeicosatrienoic acids. Here, we discuss the evidence for and against C-type natriuretic peptide (CNP), the latest candidate for a diffusible mediator.
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ROLE OF Endothelium-Derived Hyperpolarizing Factor IN ENDOTHELIAL DYSFUNCTION DURING DIABETES
Clinical and experimental pharmacology & physiology, 2005Co-Authors: Sharyn M. Fitzgerald, Barbara K Kemp-harper, Marianne Tare, Helena C. ParkingtonAbstract:1. Under normal conditions, the endothelium plays a major role in the maintenance of vasodilatory tone via the production of Endothelium-Derived vasodilator agents, such as prostacyclin, nitric oxide and Endothelium-Derived Hyperpolarizing Factor (EDHF). Inhibition of endothelium-dependent relaxation features prominently in a range of cardiovascular diseases, including hypertension, coronary artery disease and diabetes. 2. Endothelium-Derived Hyperpolarizing Factor is a prominent vasodilator, particularly in smaller arteries and arterioles. There is now emerging evidence to suggest that EDHF may play a role in the endothelial dysfunction in diabetes. 3. Since the first description of endothelium-dependent hyperpolarization some 20 years ago, it has emerged that EDHF is heterogeneous in nature, consisting of diffusible Factors and contact-mediated mechanisms. The specific identity of EDHF in any particular vascular bed may influence the impact of diabetes on vascular function. 4. There is accumulating evidence in diabetic rat models and humans showing impaired EDHF activity in small resistance vessels. In contrast, studies in mice suggest that EDHF activity is actually enhanced under diabetic conditions. 5. It is clear that alterations in EDHF activity may have an important contribution in diabetes, more specifically in contributing to microvascular complications observed under diabetic conditions.
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Involvement of Myoendothelial Gap Junctions in the Actions of Endothelium-Derived Hyperpolarizing Factor
Circulation research, 2002Co-Authors: Shaun L. Sandow, Caryl E. Hill, Marianne Tare, Harold A. Coleman, Helena C. ParkingtonAbstract:The nature of the vasodilator Endothelium-Derived Hyperpolarizing Factor (EDHF) is controversial, putatively involving diffusible Factors and/or electrotonic spread of hyperpolarization generated in the endothelium via myoendothelial gap junctions (MEGJs). In this study, we investigated the relationship between the existence of MEGJs, endothelial cell (EC) hyperpolarization, and EDHF-attributed smooth muscle cell (SMC) hyperpolarization in two different arteries: the rat mesenteric artery, where EDHF-mediated vasodilation is prominent, and the femoral artery, where there is no EDHF-dependent relaxation. In the rat mesenteric artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization of both ECs and SMCs, and characteristic pentalaminar MEGJs were found connecting the two cell layers. In contrast, in the femoral artery, ACh evoked hyperpolarization in only ECs but not in SMCs, and no MEGJs were present. Selective hyperpolarization of ECs or SMCs evoked hyperpolarization in the other cell type in the mesenteric artery but not in the femoral artery. Disruption of gap junctional coupling using the peptide Gap 27 markedly reduced the ACh-induced hyperpolarization in SMCs, but not in ECs, of the mesenteric artery. These results show that transfer of EC hyperpolarization or of a small molecule to SMCs through MEGJs is essential and sufficient to explain EDHF.
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Myoendothelial electrical coupling in arteries and arterioles and its implications for Endothelium-Derived Hyperpolarizing Factor.
Clinical and experimental pharmacology & physiology, 2002Co-Authors: Harold A. Coleman, Marianne Tare, Helena C. ParkingtonAbstract:1. Considerable progress has been made over the past decade in evaluating the presence of electrical coupling between the endothelial and smooth muscle layers of blood vessels, prompted, in part, by ultrastructural evidence for the presence of myoendothelial junctions. 2. In a variety of vessels ranging in size from conduit arteries down to small arterioles, action potentials have been recorded from endothelial cells that were associated with constriction of the vessels and/or occurred in synchrony with and were indistinguishable from action potentials recorded from the smooth muscle. From these results, it is now firmly established that myoendothelial electrical coupling occurs in at least some blood vessels. 3. Spread of Hyperpolarizing current from the endothelium to the smooth muscle is the most likely explanation of the smooth muscle hyperpolarization attributed to Endothelium-Derived Hyperpolarizing Factor. Because this hyperpolarization can evoke considerable relaxation of the smooth muscle, myoendothelial electrical coupling has important implications for endothelial regulation of the contractile activity of blood vessels.
Qin Yang - One of the best experts on this subject based on the ideXlab platform.
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Activation of canonical transient receptor potential channels preserves Ca2+ entry and Endothelium-Derived Hyperpolarizing Factor–mediated function in vitro in porcine coronary endothelial cells and coronary arteries under conditions of hyperkalemia
The Journal of thoracic and cardiovascular surgery, 2014Co-Authors: Qin Yang, Junhao Huang, Xiaoqiang Yao, Malcolm J. UnderwoodAbstract:Objectives Although membrane depolarization by hyperkalemia is known to reduce Ca 2+ influx in endothelial cells, the mechanism by which endothelial Ca 2+ channel is affected by hyperkalemia remains poorly studied. We studied the effect of hyperkalemia on canonical transient receptor potential channels, in particular canonical transient receptor potential channel 3, in modulation of endothelial intracellular Ca 2+ concentration. Endothelium-Derived Hyperpolarizing Factor–mediated function is Ca 2+ dependent, and hyperkalemic cardioplegia/organ preservation solutions impair Endothelium-Derived Hyperpolarizing Factor–mediated function. We explored the role of canonical transient receptor potential channel 3 in Endothelium-Derived Hyperpolarizing Factor–mediated function and investigated whether modulation of these channels preserves endothelial Ca 2+ influx and Endothelium-Derived Hyperpolarizing Factor–mediated function under the condition of hyperkalemic/cardioplegic exposure. Methods Intracellular Ca 2+ concentration was measured with fluorescent dye in primary cultured porcine coronary endothelial cells exposed to hyperkalemic/cardioplegic solutions containing mild to extreme high K + concentration. Endothelium-Derived Hyperpolarizing Factor–mediated relaxation under hyperkalemic/cardioplegic exposure was studied in small porcine coronary arteries in a myograph in the presence of cyclooxygenase and nitric oxide synthase inhibitors and nitric oxide scavenger. Results Canonical transient receptor potential channel 3 blocker inhibited bradykinin-induced Ca 2+ influx and attenuated Endothelium-Derived Hyperpolarizing Factor–mediated response. Hyperkalemic exposure inhibited canonical transient receptor potential channel 3–mediated Ca 2+ influx in a K + concentration-dependent manner (120 > 20 > 10 mmol/L). Ca 2+ influx decreased in porcine coronary endothelial cells exposed to histidine-tryptophan-ketoglutarate, St Thomas' Hospital, and University of Wisconsin solutions that contained mild (10 mmol/L), moderate (20 mmol/L), and extreme high (125 mmol/L) K + concentration, respectively. Canonical transient receptor potential channel activator prevented the reduction of Ca 2+ influx in porcine coronary endothelial cells exposed to solutions containing mild to moderate high [K + ] o and restored Endothelium-Derived Hyperpolarizing Factor–mediated response that was impaired by hyperkalemic exposure. Conclusions Canonical transient receptor potential channel 3 is involved in Endothelium-Derived Hyperpolarizing Factor–mediated function in coronary arteries. Hyperkalemia inhibited canonical transient receptor potential channel 3–mediated Ca 2+ influx in endothelial cells. Canonical transient receptor potential channel activation restores Ca 2+ influx suppressed by hyperkalemia and prevents dysfunction of Endothelium-Derived Hyperpolarizing Factor.
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arrest in a porcine model cardioplegic Endothelium-Derived Hyperpolarizing Factor in coronary arteries during Protective effect of magnesium on the endothelial function mediated by
2013Co-Authors: Qin Yang, Wei Zou, Yao-chung Liu, Anthony P.c. YimAbstract:J Thorac Cardiovasc Surg 2002;124:361-370 Qin Yang, Yao-Chung Liu, Wei Zou, Anthony P. C. Yim and Guo-Wei He arrest in a porcine model Endothelium-Derived Hyperpolarizing Factor in coronary arteries during cardioplegicProtective effect of magnesium on the endothelial function mediated byhttp://jtcs.ctsnetjournals.org/cgi/content/full/124/2/361 on the World Wide Web at: The online version of this article, along with updated information and services, is located
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The significance of Endothelium-Derived Hyperpolarizing Factor in the human circulation.
Current vascular pharmacology, 2007Co-Authors: Qin Yang, Anthony P.c. YimAbstract:Although nitric oxide (NO) is recognized as the primary vasodilator derived from vascular endothelium in regulating the vascular tone, another Factor, i.e. the Endothelium-Derived Hyperpolarizing Factor (EDHF), has recently gained much attention and has been demonstrated to participate in vasodilatation in various blood vessels from different species, despite its unidentified nature. Most of the studies were conducted in animals and the knowledge of this Factor in the human vasculature is relatively limited. This review attempts to address the relevance of EDHF-mediated function in humans with the possible identity of EDHF and mechanisms involved. We consider the human vasculature where EDHF involvement has been documented including the systemic, coronary, and visceral (gastrointestinal, renal and reproductive) circulation. In these vascular systems, EDHF plays a role under physiological conditions either as another mechanism or as the “back-up” for NO. Furthermore, the contribution of EDHF changes under certain physiological conditions, such as ageing and pregnancy. In addition, altered EDHF function has been suggested in various pathological conditions including heart diseases, atherosclerosis, hypertension, diabetes, eclampsia, glaucoma, chronic renal failure, erectile dysfunction and ischemia-reperfusion period during open heart surgery. Pharmacological agents such as potassium channel openers or cytochrome P450 metabolites have been used to either protect or recover EDHF-dependent mechanisms. To further develop new therapeutic strategies that target EDHF, a better understanding is essential with regard to the function of EDHF under pathophysiological conditions in humans. Furthermore, the interaction between NO and EDHF as well as their relative contributions in various conditions are critical.
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Electrophysiologic and mechanical evidence of superiority of Hyperpolarizing versus depolarizing cardioplegia in protection of Endothelium-Derived Hyperpolarizing Factor-mediated endothelial function: a study in coronary resistance arteries.
The Journal of thoracic and cardiovascular surgery, 2004Co-Authors: Anthony P.c. Yim, Qin Yang, Rong Zheng ZhangAbstract:Abstract Objective The advantages of Hyperpolarizing cardioplegia with potassium-channel openers versus depolarizing cardioplegia have been suggested but not demonstrated in coronary microarteries. This study examined the simultaneous electric and tonic alteration of coronary microarteries at the cellular level during and after exposure to depolarizing cardioplegia or Hyperpolarizing cardioplegia, with emphasis on Endothelium-Derived Hyperpolarizing Factor–mediated relaxation and hyperpolarization. Methods Porcine coronary microarteries (diameter, approximately 200-400 μm) were incubated with depolarizing cardioplegia (20 mmol/L KCl) or Hyperpolarizing cardioplegia (10 μmol/L aprikalim) for 1 hour. Cellular membrane potential with a glass microelectrode in a coronary smooth muscle cell and isometric force of the muscle were simultaneously measured in a myograph. Results Depolarizing cardioplegia incubation produced a stable contraction (from 4.9 ± 0.3 mN to 7.3 ± 0.4 mN) and depolarization (from −51 ± 1 mV to −41 ± 2 mV). In contrast, Hyperpolarizing cardioplegia relaxed (from 4.8 ± 0.3 mN to 3.5 ± 0.3 mN) and hyperpolarized (from −51 ± 2 mV to −56 ± 1 mV) the smooth muscle. After exposure to depolarizing cardioplegia, the bradykinin-induced, Endothelium-Derived Hyperpolarizing Factor–mediated relaxation reduced from 66.2% ± 5.0% to 18.4% ± 3.7% ( P P G -nitro-l-arginine. In contrast, Hyperpolarizing cardioplegia did not affect the bradykinin-induced responses. Conclusions In the coronary microarteries, exposure to Hyperpolarizing cardioplegia preserves whereas depolarizing cardioplegia reduces the Endothelium-Derived Hyperpolarizing Factor–mediated electric (hyperpolarization) and mechanical (relaxation) responses. Thus Hyperpolarizing cardioplegia is superior to depolarizing cardioplegia in protecting the endothelial function in the coronary microcirculation.
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Impaired Endothelium-Derived Hyperpolarizing Factor-mediated relaxation in porcine pulmonary microarteries after cold storage with Euro-Collins and University of Wisconsin solutions.
The Journal of thoracic and cardiovascular surgery, 2003Co-Authors: Wei Zou, Qin Yang, Anthony P.c. YimAbstract:Abstract Background Endothelium plays an important role in mediating the function of transplanted organs. The widely used University of Wisconsin solution impairs the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation in coronary arteries, but little is known about effects of lung preservation on Endothelium-Derived Hyperpolarizing Factor–mediated endothelial function. This study examined the effect of organ preservation solutions on the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation in the pulmonary microarteries (diameter 200 to 450 μm). Methods Two segments (1 as control) from the same microartery were allocated in 2 chambers of a myograph. After incubation with hyperkalemia (potassium 115 mmol/L), University of Wisconsin, or Euro-Collins solution (at 4°C for 4 hours), the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation was induced by bradykinin (−10 to −6.5 log M, n=8) or calcium ionophore (A 23187 , −9 to −5.5 log M, n=7) in U 46619 (−7.5 log M) precontracted rings in the presence of indomethacin (7 μmol/L), N G -nitro-l-arginine (300 μmol/L), and oxyhemoglobin (20 μmol/L). Results Exposure to hyperkalemia and storage with Euro-Collins or University of Wisconsin solution significantly decreased the relaxation to bradykinin (51.9 ± 8.4% vs 60.3 ± 6.1%, P = .02 or 49.3 ± 7.3% vs 65.2 ± 3.5%, P = .04) or A 23187 (12.5 ± 0.02% vs 33.8 ± 0.07%, P = .02 or 13.2 ± 0.03% vs 31.0 ± 0.05%, P = .03%). Conclusions Endothelium-Derived Hyperpolarizing Factor plays an important role in porcine pulmonary microarteries, and the Endothelium-Derived Hyperpolarizing Factor–mediated relaxation is impaired when the lung is preserved with University of Wisconsin or Euro-Collins solution. This impairment may affect the lung function during the reperfusion period after lung transplantation.
Shaun L. Sandow - One of the best experts on this subject based on the ideXlab platform.
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C-type natriuretic peptide: a new Endothelium-Derived Hyperpolarizing Factor?
Trends in pharmacological sciences, 2007Co-Authors: Shaun L. Sandow, Marianne TareAbstract:Vascular relaxation mediated by Endothelium-Derived Hyperpolarizing Factor (EDHF) is important for resistance artery function and is underpinned by hyperpolarization of the smooth muscle cells of the blood vessel wall. Debate surrounds the identity of EDHF and its mechanism of action, with the consensus being that there is no universal EDHF. Regional differences in vascular function reflect the complex mechanisms of EDHF. Two primary mechanistic pathways are implicated: (i) myoendothelial gap junctions mediating the spread of endothelial cell hyperpolarization or small signaling molecules (or both) to the smooth muscle; and (ii) diffusible mediators released from the endothelium, including K+ and epoxyeicosatrienoic acids. Here, we discuss the evidence for and against C-type natriuretic peptide (CNP), the latest candidate for a diffusible mediator.
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Factors, fiction and endothelium‐derived Hyperpolarizing Factor
Clinical and experimental pharmacology & physiology, 2004Co-Authors: Shaun L. SandowAbstract:1. The principal mediators of vascular tone are neural, endothelial and physical stimuli that result in the initiation of dilator and constrictor responses to facilitate the control of blood pressure. Two primary vasodilatory stimuli produced by the endothelium are nitric oxide (NO) and prostaglandins. An additional endothelium-dependent vasodilatory mechanism is characterized as the hyperpolarization-mediated relaxation that remains after the inhibition of the synthesis of NO and prostaglandins. This mechanism is due to the action of a so-called Endothelium-Derived Hyperpolarizing Factor (EDHF) and is dependent on either the release of diffusible Factor(s) and/or to a direct contact-mediated mechanism. 2. Most evidence supports the concept that 'EDHF' activity is dependent on contact-mediated mechanisms. This involves the transfer of an Endothelium-Derived electrical current, as an Endothelium-Derived hyperpolarization (EDH), through direct heterocellular coupling of endothelial cells and smooth muscle cells via myoendothelial gap junctions (MEGJ). However, there is a lack of consensus with regard to the nature and mechanism of action of EDHF/EDH (EDH(F)), which has been shown to vary within and between vascular beds, as well as among species, strains, sex and during development, ageing and disease. 3. In addition to actual heterogeneity in EDH(F), further heterogeneity has resulted from the less-than-optimal design, analysis and interpretation of data in some key papers in the EDHF literature; with such views being perpetuated in the subsequent literature. 4. The focus of the present brief review is to examine what Factors are proposed as EDH(F) and highlight the correlative structural and functional studies from our laboratory that demonstrate an integral role for MEGJ in the conduction of EDH, which account for the heterogeneity in EDH(F), while incorporating the reported diffusible mechanisms in the regulation of this activity. Furthermore, in addition to the reported heterogeneity in the nature and mechanism of action of EDH(F), the contribution of experimental design and technique to this heterogeneity will be examined.
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Structure, Function, and Endothelium-Derived Hyperpolarizing Factor in the Caudal Artery of the SHR and WKY Rat
Arteriosclerosis thrombosis and vascular biology, 2003Co-Authors: Shaun L. Sandow, Narelle J. Bramich, Hari Priya Bandi, Nicole M. Rummery, Caryl E. HillAbstract:Objective— To quantify structural and functional characteristics of the caudal artery from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats with particular reference to Endothelium-Derived Hyperpolarizing Factor (EDHF). Methods and Results— Ultrastructural studies showed that the number of myoendothelial gap junctions, smooth muscle cell (SMC) layers, and medial cross-sectional area were significantly greater in SHR than WKY. Intracellular dye labeling demonstrated hyperplasia of SMCs in SHR. Analysis of nerve-mediated excitatory junction potentials recorded in SMCs at the adventitial and luminal borders demonstrated decreased radial coupling of SMCs in SHR. In both SHR and WKY, in the presence of N G -nitro-l-arginine methyl ester and indomethacin, acetylcholine-elicited EDHF was abolished by charybdotoxin and apamin, while iberiotoxin had no effect, implicating the involvement of small and intermediate, but not large, calcium-activated potassium channels. EDHF was abolished by Gap-mimetic peptides, 18β-glycyrrhetinic acid, and endothelial removal but not affected by the NO scavengers hydroxocobalamin and carboxy-PTIO. Conclusions— Significant differences in SMC morphology and homocellular and heterocellular coupling exist between the caudal artery of SHR and WKY rats. In the caudal artery of SHR, significantly greater heterocellular coupling compensates for other structural changes in the media to maintain a functional role for EDHF.
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Involvement of Myoendothelial Gap Junctions in the Actions of Endothelium-Derived Hyperpolarizing Factor
Circulation research, 2002Co-Authors: Shaun L. Sandow, Caryl E. Hill, Marianne Tare, Harold A. Coleman, Helena C. ParkingtonAbstract:The nature of the vasodilator Endothelium-Derived Hyperpolarizing Factor (EDHF) is controversial, putatively involving diffusible Factors and/or electrotonic spread of hyperpolarization generated in the endothelium via myoendothelial gap junctions (MEGJs). In this study, we investigated the relationship between the existence of MEGJs, endothelial cell (EC) hyperpolarization, and EDHF-attributed smooth muscle cell (SMC) hyperpolarization in two different arteries: the rat mesenteric artery, where EDHF-mediated vasodilation is prominent, and the femoral artery, where there is no EDHF-dependent relaxation. In the rat mesenteric artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization of both ECs and SMCs, and characteristic pentalaminar MEGJs were found connecting the two cell layers. In contrast, in the femoral artery, ACh evoked hyperpolarization in only ECs but not in SMCs, and no MEGJs were present. Selective hyperpolarization of ECs or SMCs evoked hyperpolarization in the other cell type in the mesenteric artery but not in the femoral artery. Disruption of gap junctional coupling using the peptide Gap 27 markedly reduced the ACh-induced hyperpolarization in SMCs, but not in ECs, of the mesenteric artery. These results show that transfer of EC hyperpolarization or of a small molecule to SMCs through MEGJs is essential and sufficient to explain EDHF.