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      Mechanism of Contraction of Rat Isolated Tail Arteries by Hyposmotic Solutions

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          Contraction induced by hyposmotic swelling was examined in rat tail arteries mounted on a myograph containing a modified Krebs physiological saline solution (PSS) containing 50 m M mannitol (300 mosm/l). Hyposmotic swelling was induced by removing mannitol. In arteries having basal tone or arteries precontracted with K<sup>+</sup> or the thromboxane mimetic U-46619, removal of mannitol caused a concentration dependent contraction of rat tail arteries. Concurrent measurement of tension and intracellular calcium [Ca<sup>2+</sup>]<sub>i </sub>in arteries loaded with fura-2 showed that both tension and [Ca<sup>2+</sup>]<sub>i</sub> increased on exposure to a hyposmotic solution. Removal of endothelium or inhibition of nitric oxide and cyclooxygenase together did not affect contractile responses. Removal of extracellular Ca<sup>2+</sup> abolished the contractile response to hyposmotic solution and NiCl<sub>2</sub>, a nonspecific inhibitor of Ca<sup>2+</sup> influx pathways, blocked the rise in [Ca<sup>2+</sup>]<sub>i</sub> and tension in response to a hyposmotic solution. Verapamil and nisoldipine, inhibitors of Ca<sub>v</sub>1.2 (L-type) calcium channels significantly reduced the contractile response to a hyposmotic solution. Addition of NiCl<sub>2</sub> to nisoldipine caused an additional inhibition of the response to a hyposmotic solution. Inhibition of calcium release from the sarcoplasmic reticulum by ryanodine or cyclopiazonic acid (CPA) did not cause any change in the tension response to a hyposmotic solution. CPA did not significantly inhibit the response to a hyposmotic solution in the presence of N<sup>G</sup>-methyl-L-arginine, oxyhaemoglobin and indomethacin. We conclude that contraction induced by a hyposmotic solution is largely due to Ca<sub>v</sub>1.2 calcium channels although other Ca<sup>2+</sup> influx pathways also contribute.

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          Most cited references 23

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          TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes.

          Changes in membrane tension resulting from membrane stretch represent one of the key elements in blood flow regulation in vascular smooth muscle. However, the molecular mechanisms involved in the regulation of membrane stretch remain unclear. In this study, we provide evidence that a vanilloid receptor (TRPV) homologue, TRPV2 is expressed in vascular smooth muscle cells, and demonstrate that it can be activated by membrane stretch. Cell swelling caused by hypotonic solutions activated a nonselective cation channel current (NSCC) and elevated intracellular Ca2+ ([Ca2+]i) in freshly isolated cells from mouse aorta. Both of these signals were blocked by ruthenium red, an effective blocker of TRPVs. The absence of external Ca2+ abolished this increase in [Ca2+]i caused by the hypotonic stimulation and reduced the activation of NSCC. Significant immunoreactivity to mouse TRPV2 protein was detected in single mouse aortic myocytes. Moreover, the expression of TRPV2 was found in mesenteric and basilar arterial myocytes. Treatment of mouse aorta with TRPV2 antisense oligonucleotides resulted in suppression of hypotonic stimulation-induced activation of NSCC and elevation of [Ca2+]i as well as marked inhibition of TRPV2 protein expression. In Chinese hamster ovary K1 (CHO) cells transfected with TRPV2 cDNA (TRPV2-CHO), application of membrane stretch through the recording pipette and hypotonic stimulation consistently activated single NSCC. Moreover, stretch of TRPV2-CHO cells cultured on an elastic silicon membrane significantly elevated [Ca2+]i. These results provide a strong basis for our purpose that endogenous TRPV2 in mouse vascular myocytes functions as a novel and important stretch sensor in vascular smooth muscles.
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            Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle.

            Mammalian homologs of transient receptor potential (TRP) genes in Drosophila encode TRPC proteins, which make up cation channels that play several putative roles, including Ca2+ entry triggered by depletion of Ca2+ stores in endoplasmic reticulum (ER). This capacitative calcium entry (CCE) is thought to replenish Ca2+ stores and contribute to signaling in many tissues, including smooth muscle cells from main pulmonary artery (PASMCs); however, the roles of CCE and TRPC proteins in PASMCs from distal pulmonary arteries, which are thought to be the major site of pulmonary vasoreactivity, remain uncertain. As an initial test of the possibility that TRPC channels contribute to CCE and Ca2+ signaling in distal PASMCs, we measured [Ca2+]i by fura-2 fluorescence in primary cultures of myocytes isolated from rat intrapulmonary arteries (>4th generation). In cells perfused with Ca2+-free media containing cyclopiazonic acid (10 microM) and nifedipine (5 microM) to deplete ER Ca2+ stores and block voltage-dependent Ca2+ channels, restoration of extracellular Ca2+ (2.5 mM) caused marked increases in [Ca2+]i whereas MnCl2 (200 microM) quenched fura-2 fluorescence, indicating CCE. SKF-96365, LaCl3, and NiCl2, blocked CCE at concentrations that did not alter Ca2+ responses to 60 mM KCl (IC50 6.3, 40.4, and 191 microM, respectively). RT-PCR and Western blotting performed on RNA and protein isolated from distal intrapulmonary arteries and PASMCs revealed mRNA and protein expression for TRPC1, -4, and -6, but not TRPC2, -3, -5, or -7. Our results suggest that CCE through TRPC-encoded Ca2+ channels could contribute to Ca2+ signaling in myocytes from distal intrapulmonary arteries.
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              Both membrane stretch and fatty acids directly activate large conductance Ca(2+)-activated K+ channels in vascular smooth muscle cells.

              Large conductance Ca(2+)-activated K+ channels in rabbit pulmonary artery smooth muscle cells are activated by membrane stretch and by arachidonic acid and other fatty acids. Activation by stretch appears to occur by a direct effect of stretch on the channel itself or a closely associated component. In excised inside-out patches stretch activation was seen under conditions which precluded possible mechanisms involving cytosolic factors, release of Ca2+ from intracellular stores, or stretch induced transmembrane flux of Ca2+ or other ions potentially capable of activating the channel. Fatty acids also directly activate this channel. Like stretch activation, fatty acid activation occurs in excised inside-out patches in the absence of cytosolic constituents. Moreover, the channel is activated by fatty acids which, unlike arachidonic acid, are not substrates for the cyclo-oxygenase or lypoxygenase pathways, indicating that oxygenated metabolites do not mediate the response. Thus, four distinct types of stimuli (cytosolic Ca2+, membrane potential, membrane stretch, and fatty acids) can directly affect the activity of this channel.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2005
                13 April 2005
                : 42
                : 2
                : 93-100
                Clinical Pharmacology, NHLI Division, Faculty of Medicine, Imperial College London, London, UK
                83368 J Vasc Res 2005;42:93–100
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 56, Pages: 8
                Research Paper


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