Published online before print January 24, 2002, doi: 10.1161/hh0302.105662
© 2002 American Heart Association, Inc.
Reports |
Transient Receptor Potential Channels Regulate Myogenic Tone of Resistance Arteries
From the Department of Pharmacology, University of Vermont, College of Medicine, Burlington, Vt. Present address for D.G.W. is Department of Physiology and Biophysics, University of Calgary, Alberta.
Correspondence to Dr J. Brayden, Department of Pharmacology, Given Medical Building, The University of Vermont, Burlington, VT 05405. E-mail brayden{at}salus.med.uvm.edu
Abstract
Elevation of intravascular pressure causes depolarization and constriction (myogenic tone) of small arteries and arterioles, and this response is a key element in blood flow regulation. However, the nature of pressure-induced depolarization has remained elusive. In the present study, we provide evidence that a transient receptor potential channel (TRPC6) homologue has a major role in this depolarizing response to pressure. Antisense oligodeoxynucleotides to TRPC6 decreased TRPC6 protein expression and greatly attenuated arterial smooth muscle depolarization and constriction caused by elevated pressure in intact cerebral arteries. Suppressing the expression of this channel protein also reduced the current density of a major cation current in resistance artery smooth muscle cells. We propose that TRPC6 channels play an essential role in regulation of myogenic tone.
Key Words: myogenic tone • transient receptor potential channels • membrane otential • vascular smooth muscle
Originally described by Bayliss 100 years ago,1 myogenic tone develops when intravascular pressure is increased. Myogenic tone plays a key role in regulation of tissue blood flow in vivo2 and thus is of major significance in cardiovascular control. Elevation of intravascular pressure depolarizes the smooth muscle cells within the arterial wall.3 The depolarization activates dihydropyridine-sensitive (L-type) voltage-dependent Ca2+ channels,4 which leads to increased intracellular Ca2+ and vasoconstriction.
Although depolarization is key to myogenic tone, the molecular identity of the ion channels involved in this response is an important unresolved issue in vascular biology. However, the recently identified mammalian transient receptor potential channels (TRPCs)5 are good candidates for this role in arterial smooth muscle. Members of this family of cation channels are found in many different tissue types including vascular cells.6–9 The TRPC6 homologue is highly expressed in vascular smooth muscle, and these channels share many of the biophysical properties of vascular cation currents.6,7,10,11 In the present study, we have tested the hypothesis that TRPC6 channels are involved in the pressure-induced depolarization that increases myogenic tone.
Materials and Methods
Cerebellar and posterior cerebral arteries (150 µm, inner diameter) from 12- to 16-week-old Sprague-Dawley rats (Charles River Laboratories, St Constant, Canada) were studied. All animal use procedures were in accordance with institutional guidelines and approved by the Institutional Animal Care and Use Committee at the University of Vermont. For RT-PCR analysis, total RNA was extracted from arterial segments (
3 mm long) or 100 enzymatically isolated myocytes, and first-strand cDNA was synthesized. Forward and reverse primers specific for TRPC6 were TRPC6F 5'-GTGCCAAGTCCA-AAGTCCCTGC-3' and TRPC6R 5'-CTGGGCCTGCAGTA-CGTATC-3'. These primers yield a 315-bp TRPC6 cDNA product.
To assess TRPC protein expression, arteries were homogenized. Solubilized proteins were then separated by electrophoresis and detected using polyclonal antibodies to TRPC3 (anti-rabbit, 1:1000 dilution, Alomone Labs), TRPC6 (anti-rabbit 1:1000, Alomone Labs), or glyceraldehyde-3-phosphate dehydrogenase (GAPDH; anti-mouse, 1:1000, Chemicon Labs). Gels were scanned using a densitometer, and the relative densities of TRPC bands in extracts from sense- and antisense-treated arteries (normalized to GAPDH density) were compared. To verify TRPC antibody specificity, TRPC3 and TRPC6 proteins were expressed in a rabbit reticulocyte in vitro expression system and immunoblotted using TRPC3 and TRPC6 antibodies. No cross-reactivity of the TRPC3 or TRPC6 antibodies was noted.
For immunohistochemistry, arteries were fixed in paraformaldehyde, permeabilized in Triton X-100, and exposed to primary (rabbit anti-TRPC3, 1:200 dilution; rabbit anti-TRPC6, 1:500 dilution) and secondary (Cy3-anti-rabbit IgG, 1:500 dilution, Jackson ImmunoResearch) antibodies. Arteries were viewed using a BioRad 1000 confocal microscope.
Oligodeoxynucleotides (ODNs) were designed based on conserved regions between mouse and human TRPC6 sequences and were as follows: antisense, 5'-GGAGTTCAGACTGGCTAGGG-3' and 5'-GTGAAGGAGGCTGCGTGTGC-3'; sense, 5'-CCCT-AGCCAGTCTGAACTCC-3' and 5'-GCACACGCAGCCTC-CTTCAC-3' (Annovis Inc). To assess cellular localization, fluorescein isothiocyanate was conjugated to the 5' terminal nucleotides. ODNs were introduced into intact cerebral arteries using a reversible permeabilization procedure.12 Arteries (unpressurized) were then organ-cultured for 4 to 5 days in DMEM/F-12 (serum-free) culture medium.
After organ culture, arteries were mounted in an arteriograph, endothelial cells were removed, and diameter and membrane potential were monitored, as previously described.3,10 In addition, cation currents were measured in smooth muscle cells isolated from TRPC6 sense- and antisense-treated arteries using conventional whole-cell patch-clamp techniques.10
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
Results and Discussion
Message for TRPC6 was identified in smooth muscle cells of cerebral arteries (Figure 1A). Western blot analyses yielded protein bands of the appropriate molecular mass for TRPC613 (105 kDa) (Figure 1B). Immunofluorescent labeling of intact cerebral arteries revealed a circumferential staining pattern for TRPC6, consistent with localization of TRPC6 to arterial smooth muscle (Figure 1C) (labeling was absent when antibody was preabsorbed by TRPC6 antigen peptide). For comparison, immunofluorescent labeling of another major TRPC, TRPC3, was also assessed and was clearly present in the smooth muscle cells (Figure 1C).
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To assess the functional role of TRPC6 in cerebral arteries, we used an oligonucleotide approach to decrease the expression of TRPC6 in cerebral artery myocytes. TRPC6 ODNs were clearly present in arterial smooth muscle cells after the permeabilization procedures (Figure 2A). TRPC6 antisense ODNs reduced the expression of TRPC6 protein in cerebral arteries by 58±6% compared with sense-treated arteries (P<0.05) (Figures 2B and 2C). This effect appeared to be specific because TRPC3 expression was unaffected by the antisense ODNs directed against TRPC6.
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To obtain direct evidence for the functional roles of TRPC6 channels in cerebral arterial smooth muscle, we examined the effects of contractile stimuli on the diameter of TRPC6 sense- and antisense-treated arteries. Membrane depolarization by elevation of external K+ to 60 mmol/L constricts cerebral arteries by 60% through activation of voltage-dependent Ca2+ channels and elevation of internal [Ca2+].14 In the present study, antisense and sense ODNs did not affect the K+-induced constrictions (decrease in resting diameter: sense, 52±3%; antisense, 56±2%). This finding indicated that treatment with ODNs did not have generalized inhibitory effects on arterial contractility or inhibit voltage-dependent calcium channels. In contrast, vasoconstriction induced by elevating intravascular pressure was inhibited by 70% to 80% in TRPC6 antisense compared with sense-treated arteries (Figures 3A and 3B). Furthermore, TRPC6 antisense ODNs reduced pressure-induced depolarization of the arterial smooth muscle cells by 60% compared with sense-treated arteries, but did not affect the membrane potential at low pressure (Figure 3C). These findings are consistent with pressure-causing vasoconstriction through activation of TRPC6 cation channels.
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Sodium-permeable nonselective cation channels are present in arterial smooth muscle cells.10,11 In myogenic cerebral arteries, currents through these channels were elevated by cell swelling, a stimulus that seems to mimic the effects of elevated intravascular pressure.10 If these currents reflect activation of TRPC6 channels, then their activity should be suppressed by treatment with TRPC6 antisense ODNs. Indeed, we found that the density of the cation current was substantially reduced in smooth muscle cells from arteries exposed to TRPC6 antisense versus sense ODNs (Figures 3D and 3E).
Inhibition of voltage-dependent potassium (Kv) channels causes substantial depolarization of arterial smooth muscle cells.14 As a control, we tested the effects of the ODNs on Kv currents and observed no differences in cells from sense- versus antisense-treated arteries (Kv current density at +100 mV: sense-treated, 26.1±1.0 pA/pF, n=4; antisense-treated, 27.0±0.8 pA/pF, n=3). This indicates that the effect of TRPC6 antisense ODNs on the cation currents was specific and lends further support for a major role of TRPC6 in pressure-induced depolarization.
Although TRPC channels are present in cells in the cardiovascular system,5–9 their functional roles in these cells have been unclear. In the present study, we have demonstrated that TRPC6 is centrally involved in the mechanisms underlying myogenic depolarization and tone. This conclusion is based on the ability of TRPC6 antisense ODNs to (1) decrease (60%) TRPC6 protein expression, (2) attenuate pressure-induced depolarization (65%) and vasoconstriction (75%) in intact arteries, and (3) reduce (47%) the density of a cation current, which is involved in pressure-induced myogenic depolarization.10 Consistent with the proposed role of TRPC6 in regulation of arterial tone, TRPC6 channels,6 cerebral arterial cation currents,10 and pressure-induced depolarization10 are all inhibited by low micromolar concentrations of the cation channel blocker Gd+.3
Myogenic tone has been observed in resistance arteries in many vascular beds and seems to be involved in autoregulation of blood flow in the microcirculation of the brain, kidney, and heart.2 The mechanisms by which pressure activates TRPC6 channels are not known. TRPC channels have been shown to be activated by phospholipase C (PLC),5 possibly through direct actions of diacylglycerol (DAG)6,13,15 generated via PLC activity. Pressure increases PLC activity16 as well as the concentration of diacylglycerol17 in isolated cerebral arteries. We therefore propose the following mechanism by which myogenic tone could be activated: 
intravascular pressure 
PLC activation DAG activity TRPC activity membrane depolarization opening of VDCC intracellular [Ca2+] myogenic tone. The data from this study also suggest that TRPC6 is a potential target for pharmacological manipulation of vascular tone and peripheral resistance. Therefore, these findings could be of substantial relevance in the development of strategies to treat diseases associated with excessive vasoconstriction, such as hypertension and vasospasm.
Acknowledgments
This work was supported by the NIH (HL58231 to J.E.B.; HL44455 and HL63722 to M.T.N.), the Canadian Institute of Health Research (D.W.), and Totman Medical Research Trust. We thank M. Gomez, A. Stevenson, and R. Inoue for technical advice, S. Brett Welsh for technical assistance, and M. Taylor for comments on the manuscript.
Received May 23, 2001; revision received January 14, 2002; accepted January 14, 2002.
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M. Freichel, R. Vennekens, J. Olausson, S. Stolz, S. E Philipp, P. Weissgerber, and V. Flockerzi Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies J. Physiol., August 15, 2005; 567(1): 59 - 66. [Abstract] [Full Text] [PDF]
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R. E Haddock and C. E Hill Rhythmicity in arterial smooth muscle J. Physiol., August 1, 2005; 566(3): 645 - 656. [Abstract] [Full Text] [PDF]
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L. A. Martinez-Lemus, T. Crow, M. J. Davis, and G. A. Meininger {alpha}v{beta}3- and {alpha}5{beta}1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H322 - H329. [Abstract] [Full Text] [PDF]
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S. A. Reading, S. Earley, B. J. Waldron, D. G. Welsh, and J. E. Brayden TRPC3 mediates pyrimidine receptor-induced depolarization of cerebral arteries Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2055 - H2061. [Abstract] [Full Text] [PDF]
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A. Bergdahl, M. F. Gomez, A.-K. Wihlborg, D. Erlinge, A. Eyjolfson, S.-Z. Xu, D. J. Beech, K. Dreja, and P. Hellstrand Plasticity of TRPC expression in arterial smooth muscle: correlation with store-operated Ca2+ entry Am J Physiol Cell Physiol, April 1, 2005; 288(4): C872 - C880. [Abstract] [Full Text] [PDF]
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S. Yano, T. Ishikawa, H. Tsuda, K. Obara, and K. Nakayama Ionic mechanism for contractile response to hyposmotic challenge in canine basilar arteries Am J Physiol Cell Physiol, March 1, 2005; 288(3): C702 - C709. [Abstract] [Full Text] [PDF]
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E Rousseau, M. Cloutier, C. Morin, and S. Proteau Capsazepine, a vanilloid antagonist, abolishes tonic responses induced by 20-HETE on guinea pig airway smooth muscle Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L460 - L470. [Abstract] [Full Text] [PDF]
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J. Shi, E. Mori, Y. Mori, M. Mori, J. Li, Y. Ito, and R. Inoue Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells J. Physiol., December 1, 2004; 561(2): 415 - 432. [Abstract] [Full Text] [PDF]
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S. Earley, T. C. Resta, and B. R. Walker Disruption of smooth muscle gap junctions attenuates myogenic vasoconstriction of mesenteric resistance arteries Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2677 - H2686. [Abstract] [Full Text] [PDF]
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N. Kunichika, Y. Yu, C. V. Remillard, O. Platoshyn, S. Zhang, and J. X.-J. Yuan Overexpression of TRPC1 enhances pulmonary vasoconstriction induced by capacitative Ca2+ entry Am J Physiol Lung Cell Mol Physiol, November 1, 2004; 287(5): L962 - L969. [Abstract] [Full Text] [PDF]
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S. Zhang, C. V. Remillard, I. Fantozzi, and J. X.-J. Yuan ATP-induced mitogenesis is mediated by cyclic AMP response element-binding protein-enhanced TRPC4 expression and activity in human pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, November 1, 2004; 287(5): C1192 - C1201. [Abstract] [Full Text] [PDF]
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A. Ahmed, C. M. Waters, C. W. Leffler, and J. H. Jaggar Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2061 - H2069. [Abstract] [Full Text] [PDF]
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H. A. Drummond, D. Gebremedhin, and D. R. Harder Degenerin/Epithelial Na+ Channel Proteins: Components of a Vascular Mechanosensor Hypertension, November 1, 2004; 44(5): 643 - 648. [Abstract] [Full Text] [PDF]
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S. Earley, B. J. Waldron, and J. E. Brayden Critical Role for Transient Receptor Potential Channel TRPM4 in Myogenic Constriction of Cerebral Arteries Circ. Res., October 29, 2004; 95(9): 922 - 929. [Abstract] [Full Text] [PDF]
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D. J. Beech, K. Muraki, and R. Flemming Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP J. Physiol., September 15, 2004; 559(3): 685 - 706. [Abstract] [Full Text] [PDF]
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M.-J. Lin, G. P.H. Leung, W.-M. Zhang, X.-R. Yang, K.-P. Yip, C.-M. Tse, and J. S.K. Sham Chronic Hypoxia-Induced Upregulation of Store-Operated and Receptor-Operated Ca2+ Channels in Pulmonary Arterial Smooth Muscle Cells: A Novel Mechanism of Hypoxic Pulmonary Hypertension Circ. Res., September 3, 2004; 95(5): 496 - 505. [Abstract] [Full Text] [PDF]
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 J.-B. Huang, A. L. Kindzelskii, A. J. Clark, and H. R. Petty Identification of Channels Promoting Calcium Spikes and Waves in HT1080 Tumor Cells: Their Apparent Roles in Cell Motility and Invasion Cancer Res., April 1, 2004; 64(7): 2482 - 2489. [Abstract] [Full Text] [PDF]
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M. Konrad, K. P. Schlingmann, and T. Gudermann Insights into the molecular nature of magnesium homeostasis Am J Physiol Renal Physiol, April 1, 2004; 286(4): F599 - F605. [Abstract] [Full Text] [PDF]
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J. Wang, L. A. Shimoda, and J. T. Sylvester Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L848 - L858. [Abstract] [Full Text] [PDF]
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 L. G. Babich, C.-Y. Ku, H. W.J. Young, H. Huang, M. R. Blackburn, and B. M. Sanborn Expression of Capacitative Calcium TrpC Proteins in Rat MyometriumDuring Pregnancy Biol Reprod, April 1, 2004; 70(4): 919 - 924. [Abstract] [Full Text] [PDF]
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C. S. Facemire, P. J. Mohler, and W. J. Arendshorst Expression and relative abundance of short transient receptor potential channels in the rat renal microcirculation Am J Physiol Renal Physiol, March 1, 2004; 286(3): F546 - F551. [Abstract] [Full Text]
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 R. L. Corteling, S. Li, J. Giddings, J. Westwick, C. Poll, and I. P. Hall Expression of Transient Receptor Potential C6 and Related Transient Receptor Potential Family Members in Human Airway Smooth Muscle and Lung Tissue Am. J. Respir. Cell Mol. Biol., February 1, 2004; 30(2): 145 - 154. [Abstract] [Full Text] [PDF]
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M.-G. Feng, M. Li, and L. G. Navar T-type calcium channels in the regulation of afferent and efferent arterioles in rats Am J Physiol Renal Physiol, February 1, 2004; 286(2): F331 - F337. [Abstract] [Full Text] [PDF]
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A. Dietrich, M. Mederos y Schnitzler, J. Emmel, H. Kalwa, T. Hofmann, and T. Gudermann N-Linked Protein Glycosylation Is a Major Determinant for Basal TRPC3 and TRPC6 Channel Activity J. Biol. Chem., November 28, 2003; 278(48): 47842 - 47852. [Abstract] [Full Text] [PDF]
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K. Muraki, Y. Iwata, Y. Katanosaka, T. Ito, S. Ohya, M. Shigekawa, and Y. Imaizumi TRPV2 Is a Component of Osmotically Sensitive Cation Channels in Murine Aortic Myocytes Circ. Res., October 31, 2003; 93(9): 829 - 838. [Abstract] [Full Text] [PDF]
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A. Bergdahl, M. F. Gomez, K. Dreja, S.-Z. Xu, M. Adner, D. J. Beech, J. Broman, P. Hellstrand, and K. Sward Cholesterol Depletion Impairs Vascular Reactivity to Endothelin-1 by Reducing Store-Operated Ca2+ Entry Dependent on TRPC1 Circ. Res., October 31, 2003; 93(9): 839 - 847. [Abstract] [Full Text] [PDF]
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K. S. Park, Y. Kim, Y.-H. Lee, Y. E. Earm, and W.-K. Ho Mechanosensitive Cation Channels in Arterial Smooth Muscle Cells Are Activated by Diacylglycerol and Inhibited by Phospholipase C Inhibitor Circ. Res., September 19, 2003; 93(6): 557 - 564. [Abstract] [Full Text] [PDF]
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M. Cloutier, S. Campbell, N. Basora, S. Proteau, M. D. Payet, and E. Rousseau 20-HETE inotropic effects involve the activation of a nonselective cationic current in airway smooth muscle Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L560 - L568. [Abstract] [Full Text] [PDF]
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N. Basora, G. Boulay, L. Bilodeau, E. Rousseau, and M. D. Payet 20-Hydroxyeicosatetraenoic Acid (20-HETE) Activates Mouse TRPC6 Channels Expressed in HEK293 Cells J. Biol. Chem., August 22, 2003; 278(34): 31709 - 31716. [Abstract] [Full Text] [PDF]
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Y. Yu, M. Sweeney, S. Zhang, O. Platoshyn, J. Landsberg, A. Rothman, and J. X.-J. Yuan PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression Am J Physiol Cell Physiol, February 1, 2003; 284(2): C316 - C330. [Abstract] [Full Text] [PDF]
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G. Lagaud, N. Gaudreault, E. D. W. Moore, C. van Breemen, and I. Laher Pressure-dependent myogenic constriction of cerebral arteries occurs independently of voltage-dependent activation Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2187 - H2195. [Abstract] [Full Text] [PDF]
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D. F. Slish, D. G. Welsh, and J. E. Brayden Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2196 - H2201. [Abstract] [Full Text] [PDF]
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M. Ishiguro, C. B. Puryear, E. Bisson, C. M. Saundry, D. J. Nathan, S. R. Russell, B. I. Tranmer, and G. C. Wellman Enhanced myogenic tone in cerebral arteries from a rabbit model of subarachnoid hemorrhage Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2217 - H2225. [Abstract] [Full Text] [PDF]
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S. Veerareddy, C.-L. M. Cooke, P. N. Baker, and S. T. Davidge Vascular adaptations to pregnancy in mice: effects on myogenic tone Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2226 - H2233. [Abstract] [Full Text] [PDF]
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Y. P. R. Jarajapu and H. J. Knot Role of phospholipase C in development of myogenic tone in rat posterior cerebral arteries Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2234 - H2238. [Abstract] [Full Text] [PDF]
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E. VanBavel, O. Sorop, D. Andreasen, M. Pfaffendorf, and B. L. Jensen Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2239 - H2243. [Abstract] [Full Text] [PDF]
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J. Zhang, W. G. Wier, and M. P. Blaustein Mg2+ blocks myogenic tone but not K+-induced constriction: role for SOCs in small arteries Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2692 - H2705. [Abstract] [Full Text] [PDF]
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