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      Magnesium lithospermate B dilates mesenteric arteries by activating BK Ca currents and contracts arteries by inhibiting K V currents

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          Abstract

          Aim:

          To examine the involvement of K + channels and endothelium in the vascular effects of magnesium lithospermate B (MLB), a hydrophilic active component of Salviae miltiorrhiza Radix.

          Methods:

          Isolated rat mesenteric artery rings were employed to investigate the effects of MLB on KCl- or norepinephrine-induced contractions. Conventional whole-cell patch-clamp technique was used to study the effects of MLB on K + currents in single isolated mesenteric artery myocytes.

          Results:

          MLB produced a concentration-dependent relaxation in mesenteric artery rings precontracted by norepinephrine (1 μmol/L) with an EC 50 of 111.3 μmol/L. MLB-induced relaxation was reduced in denuded artery rings with an EC 50 of 224.4 μmol/L. MLB caused contractions in KCl-precontracted artery rings in the presence of N-nitro- L-arginine methyl ester ( L-NAME) with a maximal value of 130.3%. The vasodilatory effect of MLB was inhibited by tetraethylammonium (TEA) in both intact and denuded artery rings. In single smooth muscle cells, MLB activated BK Ca currents (EC 50 156.3 μmol/L) but inhibited K V currents (IC 50 26.1 μmol/L) in a voltage- and concentration-dependent manner.

          Conclusion:

          MLB dilated arteries by activating BK Ca channels in smooth muscle cells and increasing NO release from endothelium, but it also contracted arteries precontracted with KCl in the presence of L-NAME.

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          Most cited references26

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          Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.

          1. The extracellular patch clamp method, which first allowed the detection of single channel currents in biological membranes, has been further refined to enable higher current resolution, direct membrane patch potential control, and physical isolation of membrane patches. 2. A description of a convenient method for the fabrication of patch recording pipettes is given together with procedures followed to achieve giga-seals i.e. pipette-membrane seals with resistances of 10(9) - 10(11) omega. 3. The basic patch clamp recording circuit, and designs for improved frequency response are described along with the present limitations in recording the currents from single channels. 4. Procedures for preparation and recording from three representative cell types are given. Some properties of single acetylcholine-activated channels in muscle membrane are described to illustrate the improved current and time resolution achieved with giga-seals. 5. A description is given of the various ways that patches of membrane can be physically isolated from cells. This isolation enables the recording of single channel currents with well-defined solutions on both sides of the membrane. Two types of isolated cell-free patch configurations can be formed: an inside-out patch with its cytoplasmic membrane face exposed to the bath solution, and an outside-out patch with its extracellular membrane face exposed to the bath solution. 6. The application of the method for the recording of ionic currents and internal dialysis of small cells is considered. Single channel resolution can be achieved when recording from whole cells, if the cell diameter is small (less than 20 micrometer). 7. The wide range of cell types amenable to giga-seal formation is discussed.
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            Physiological roles and properties of potassium channels in arterial smooth muscle.

            This review examines the properties and roles of the four types of K+ channels that have been identified in the cell membrane of arterial smooth muscle cells. 1) Voltage-dependent K+ (KV) channels increase their activity with membrane depolarization and are important regulators of smooth muscle membrane potential in response to depolarizing stimuli. 2) Ca(2+)-activated K+ (KCa) channels respond to changes in intracellular Ca2+ to regulate membrane potential and play an important role in the control of myogenic tone in small arteries. 3) Inward rectifier K+ (KIR) channels regulate membrane potential in smooth muscle cells from several types of resistance arteries and may be responsible for external K(+)-induced dilations. 4) ATP-sensitive K+ (KATP) channels respond to changes in cellular metabolism and are targets of a variety of vasodilating stimuli. The main conclusions of this review are: 1) regulation of arterial smooth muscle membrane potential through activation or inhibition of K+ channel activity provides an important mechanism to dilate or constrict arteries; 2) KV, KCa, KIR, and KATP channels serve unique functions in the regulation of arterial smooth muscle membrane potential; and 3) K+ channels integrate a variety of vasoactive signals to dilate or constrict arteries through regulation of the membrane potential in arterial smooth muscle.
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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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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                June 2010
                10 May 2010
                : 31
                : 6
                : 665-670
                Affiliations
                [1 ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China
                Author notes
                Article
                aps201040
                10.1038/aps.2010.40
                4002966
                20453873
                0271f939-2efd-4caa-b213-d5a52a6be3ca
                Copyright © 2010 CPS and SIMM
                History
                : 17 November 2009
                : 08 March 2010
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                magnesium lithospermate b,big-conductance ca2+-activated k+ channels,mesenteric artery,endothelium

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