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      The Effects of Endothelial Factor Inhibition on the Time Course of Responses of Isolated Rat Coronary Arteries to Intraluminal Flow



      Journal of Vascular Research

      S. Karger AG

      Coronary artery, Endothelial factors, Flow

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          The aims of this study were to investigate, for the first time, the effects of endothelial factor inhibition on both the magnitude and dynamics of the response of isolated small coronary arteries to intraluminal flow. Isolated rat coronary arteries were mounted on a pressure myograph and left to develop myogenic tone. Flow was introduced and maintained until stable diameters were attained. Dilatory responses were observed which were maximal at low flow rates (5–10 µl/min) and thus shear stresses (1–2 dyn/cm<sup>2</sup>). These responses were transient in nature. Transient dilations were also observed upon cessation of flow. All responses (to 5 µl/min) were endothelium dependent and were completely abolished by addition of charybdotoxin (100 n M) and apamin (100–500 n M) suggesting an important role for a hyperpolarizing mechanism most likely involving an endothelium-derived hyperpolarizing factor. However, inhibitors of nitric oxide synthase (L-NNA; 100 µ M) or cyclo-oxygenase (indomethacin; 10 µ M) also modulated the response causing an increase and decrease in maximum vasodilation, respectively. By examining the time course we showed that both agents also made the response significantly more transient in nature. These results show that inhibition of endothelial factor pathways can influence both the magnitude and dynamics of the response of isolated rat coronary arteries to flow.

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          Most cited references 13

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          Endothelium-derived hyperpolarizing factor: where are we now?

          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 (H2O2). These different mechanisms are not necessarily exclusive and can occur simultaneously.
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            Selective COX-2 inhibition improves endothelial function in coronary artery disease.

            There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. Fourteen male patients (mean age, 66+/-3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3+/-0.4% versus 2.0+/-0.5%, P=0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0+/-1.6% versus 9.5+/-1.3%, P=0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3+/-0.4 mg/L) than after placebo (1.8+/-0.5 mg/L, P=0.019), as was oxidized LDL (43.6+/-2.4 versus 47.6+/-2.6 U/L, P=0.028), whereas prostaglandins did not change. This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.
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              Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles.

              Flow-induced dilation (FID) is dependent largely on hyperpolarization of vascular smooth muscle cells (VSMCs) in human coronary arterioles (HCA) from patients with coronary disease. Animal studies show that shear stress induces endothelial generation of hydrogen peroxide (H2O2), which is proposed as an endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that H2O2 contributes to FID in HCA. Arterioles (135+/-7 micro m, n=71) were dissected from human right atrial appendages at the time of cardiac surgery and cannulated with glass micropipettes. Changes in internal diameter and membrane potential of VSMCs to shear stress, H2O2, or to papaverine were recorded with videomicroscopy. In some vessels, endothelial H2O2 generation to shear stress was monitored directly using confocal microscopy with 2',7'-dichlorofluorescin diacetate (DCFH) or using electron microscopy with cerium chloride. Catalase inhibited FID (%max dilation; 66+/-8 versus 25+/-7%; P<0.05, n=6), whereas dilation to papaverine was unchanged. Shear stress immediately increased DCFH fluorescence in the endothelial cell layer, whereas treatment with catalase abolished the increase in fluorescence. Electron microscopy with cerium chloride revealed shear stress-induced increase in cerium deposition in intimal area surrounding endothelial cells. Exogenous H2O2 dilated (%max dilation; 97+/-1%, ED50; 3.0+/-0.7x10(-5) mol/L) and hyperpolarized HCA. Dilation to H2O2 was reduced by catalase, 40 mmol/L KCl, or charybdotoxin plus apamin, whereas endothelial denudation, deferoxamine, 1H-(1,2,4)-oxadiazole-[4,3-a]quinoxalin-1-one, or glibenclamide had no effect. These data provide evidence that shear stress induces endothelial release of H2O2 and are consistent with the idea that H2O2 is an EDHF that contributes to FID in HCA from patients with heart disease. The full text of this article is available at http://www.circresaha.org.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2007
                28 February 2007
                : 44
                : 3
                : 223-233
                Smooth Muscle Physiology Group, Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, University of Manchester, Manchester, UK
                100421 J Vasc Res 2007;44:223–233
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 35, Pages: 11
                Research Paper


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