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      20-Hydroxyeicosatetraenoic Acid Contributes to the Inhibition of K+ Channel Activity and Vasoconstrictor Response to Angiotensin II in Rat Renal Microvessels

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          Abstract

          The present study examined whether 20-hydroxyeicosatetraenoic acid (HETE) contributes to the vasoconstrictor effect of angiotensin II (ANG II) in renal microvessels by preventing activation of the large conductance Ca 2+-activated K + channel (K Ca) in vascular smooth muscle (VSM) cells. ANG II increased the production of 20-HETE in rat renal microvessels. This response was attenuated by the 20-HETE synthesis inhibitors, 17-ODYA and HET0016, a phospholipase A 2 inhibitor AACOF 3, and the AT 1 receptor blocker, Losartan, but not by the AT 2 receptor blocker, PD123319. ANG II (10 -11 to 10 -6 M) dose-dependently decreased the diameter of renal microvessels by 41 ± 5%. This effect was blocked by 17-ODYA. ANG II (10 -7 M) did not alter K Ca channel activity recorded from cell-attached patches on renal VSM cells under control conditions. However, it did reduce the NPo of the K Ca channel by 93.4 ± 3.1% after the channels were activated by increasing intracellular calcium levels with ionomycin. The inhibitory effect of ANG II on K Ca channel activity in the presence of ionomycin was attenuated by 17-ODYA, AACOF 3, and the phospholipase C (PLC) inhibitor U-73122. ANG II induced a peak followed by a steady-state increase in intracellular calcium concentration in renal VSM cells. 17-ODYA (10 -5 M) had no effect on the peak response, but it blocked the steady-state increase. These results indicate that ANG II stimulates the formation of 20-HETE in rat renal microvessels via the AT 1 receptor activation and that 20-HETE contributes to the vasoconstrictor response to ANG II by blocking activation of K Ca channel and facilitating calcium entry.

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          Most cited references 38

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          Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases.

          A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.
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            Ion channels and vascular tone.

            Ion channels in the plasma membrane of vascular muscle cells that form the walls of resistance arteries and arterioles play a central role in the regulation of vascular tone. Current evidence indicates that vascular smooth muscle cells express at least 4 different types of K(+) channels, 1 to 2 types of voltage-gated Ca(2+) channels, >/=2 types of Cl(-) channels, store-operated Ca(+) (SOC) channels, and stretch-activated cation (SAC) channels in their plasma membranes, all of which may be involved in the regulation of vascular tone. Calcium influx through voltage-gated Ca(2+), SOC, and SAC channels provides a major source of activator Ca(2+) used by resistance arteries and arterioles. In addition, K(+) and Cl(-) channels and the Ca(2+) channels mentioned previously all are involved in the determination of the membrane potential of these cells. Membrane potential is a key variable that not only regulates Ca(+2) influx through voltage-gated Ca(2+) channels, but also influences release of Ca(2+) from internal stores and Ca(2+)- sensitivity of the contractile apparatus. By controlling Ca(2+) delivery and membrane potential, ion channels are involved in all aspects of the generation and regulation of vascular tone.
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              HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme.

               T. Seki,  T Ueki,  M Watanabe (2001)
              The present study examined the inhibitory effects of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) in rat renal microsomes. The IC(50) value averaged 35+/-4 nM, whereas the IC(50) value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800+/-300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20-HETE with an IC(50) value of 8.9+/-2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4-catalysed substrates oxidation with IC(50) values of 3300, 83,900 and 71,000 nM. The IC(50) value for HET0016 on cyclo-oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20-HETE in man and rat.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                4 December 2013
                : 8
                : 12
                Affiliations
                [1 ]Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
                [2 ]Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, United States of America
                [3 ]Division of Vascular Surgery and Endovascular Services, SUNY Upstate Medical University, Syracuse, New York, United States of America
                [4 ]Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                INSERM, France
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RJR JRF. Performed the experiments: FF CWS KGM JMW MRP. Analyzed the data: FF CWS JMW MRP KGM RJR. Contributed reagents/materials/analysis tools: RJR. Wrote the manuscript: FF CWS KGM RJR JZ SPD.

                Article
                PONE-D-13-31159
                10.1371/journal.pone.0082482
                3853207

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Funding
                This work was funded in part by grants HL36279, HL29587 (RJR), RO1DK067299 (JZ) and HL089884 and HL107632 (SPD) from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
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