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Vascular large conductance calcium-activated potassium channels: Functional role and therapeutic potential

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Abstract

Large-conductance Ca2+-activated K+ channels (BKCa or maxiK channels) are expressed in different cell types. They play an essential role in the regulation of various cell functions. In particular, BKCa channels have been extensively studied in vascular smooth muscle cells, where they contribute to the control of vascular tone. They facilitate the feedback regulation against the rise of intracellular Ca2+, membrane depolarization and vasoconstriction. BKCa channels promote a K+ outward current and lead to membrane hyperpolarization. In endothelial cells expression and function of BKCa channels play an important role in the regulation of the vascular smooth muscle activity. Endothelial BKCa channels modulate the biosyntheses and release of various vasoactive modulators and regulate the membrane potential. Because of their regulatory role in vascular tone, endothelial BKCa channels have been suggested as therapeutic targets for the treatment of cardiovascular diseases. Hypertension, atherosclerosis, and diabetes are associated with altered current amplitude, open probability, and Ca2+-sensing of BKCa channels. The properties of BKCa channels and their role in endothelial and vascular smooth muscle cells would address them as potential therapeutic targets. Further studies are necessary to identify the detailed molecular mechanisms of action and to investigate selective BKCa channels openers as possible therapeutic agents for clinical use.

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References

  • Ahern GP, Hsu SF, Jackson MB (1999) Direct action of nitric oxide on rat neurohypophysil K+ channels. J Physiol 520:165–176

    PubMed  CAS  Google Scholar 

  • Ahn SC, Seol GH, Kim JA, Suh SH (2004) Characteristics and a functional implication of Ca2+-activated K+ current in mouse aortic endothelial cells. Pflugers Arch 447:426–435

    PubMed  CAS  Google Scholar 

  • Amberg GC, Bonev AD, Rossow CF, Nelson MT, Santana LF (2003) Modulation of the molecular composition of large conductance, Ca2+ activated K+ channels in vascular smooth muscle during hypertension. J Clin Invest 112:717–724

    PubMed  CAS  Google Scholar 

  • Asano M, Nomura Y, Ito K, Uyama Y, Imaizumi Y, Watanabe M (1995) Increased function of voltage-dependent Ca2+ channels and Ca2+-activated K+ channels in resting state of femoral arteries from spontaneously hypertensive rats at prehypertensive stage. J Pharmacol Exp Ther 275:775–783

    PubMed  CAS  Google Scholar 

  • Atkinson NS, Robertson GA, Ganetzky B (1991) A component of calcium-activated potassium channels encoded by the Drosophila slo locus. Science 253:551–555

    PubMed  CAS  Google Scholar 

  • Barman SA, Zhu S, White RE (2004a) Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 286:149–155

    Google Scholar 

  • Barman SA, Zhu S, White RE (2004b) PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol Lung Cell Mol Physiol 286:1275–1281

    Google Scholar 

  • Baron A, Frieden M, Chabaud F, Beny JL (1996) Ca2+ dependent non-selective cation and potassium channel activated by bradykinin in pig coronary artery endothelial cells. J Physiol 493:691–706

    PubMed  CAS  Google Scholar 

  • Beech DJ, Bolton TB (1989) Properties of the cromakalim-induced potassium conductance in smooth muscle cells isolated from the rabbit portal vein. Br J Pharmacol 98:851–864

    PubMed  CAS  Google Scholar 

  • Blatz AL, Magleby KL (1986) Single apamin-blocked Ca2+-activated K+ channels of small conductance in cultured rat skeletal muscle. Nature 323:718–720

    PubMed  CAS  Google Scholar 

  • Bolotina V, Gericke M, Bregestovski P (1991) Kinetic differences between Ca2+-dependent K+ channels in smooth muscle cells isolated from normal and atherosclerotic human aorta. Proc Biol Sci 244:51–55

    PubMed  CAS  Google Scholar 

  • Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368:850–853

    PubMed  CAS  Google Scholar 

  • Bonev AD, Jaggar JH, Rubart M, Nelson MT (1997) Activators of protein kinase C decrease Ca2+ spark frequency in smooth muscle cells from cerebral arteries. Am J Physiol 273:2090–2095

    Google Scholar 

  • Brainard AM, Miller AJ, Martens JR, England SK (2005) Maxi-K channels localized to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Am J Physiol 289:49–57

    Google Scholar 

  • Brakemeier S, Eichler J, Knorr A, Fassheber T, Kohler R, Hoyer J (2003) Modulation of Ca2+-activated K+ channel in renal artery endothelium in situ by nitric oxide and reactive oxygen species. Kidney Int 64:199–207

    PubMed  CAS  Google Scholar 

  • Bregestovski PD, Printseva OY, Serebryakov V, Stinnakre J, Turmin A, Zamoyski V (1988) Comparison of Ca2+-dependent K+ channels in the membrane of smooth muscle cells isolated from adult and foetal human aorta. Pflugers Arch 413:8–13

    PubMed  CAS  Google Scholar 

  • Brenner R, Peréz GJ, Bonev AD, Eckmann DM, Kosek JC, Wiler SW, Patterson AJ, Nelson MT, Aldrich RW (2000) Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 407:870–876

    PubMed  CAS  Google Scholar 

  • Brito PM, Mariano A, Almeida LM, Dinis TC (2006) Resveratrol affords protection against peroxynitrite-mediated endothelial cell death: a role for intracellular glutathione. Chem Biol Interact 164:157–166

    PubMed  CAS  Google Scholar 

  • Brown AM, Ellory JC, Young JD, Lew VL (1978) Calcium-activated potassium channel present in foetal red cells of the sheep but absent from reticulocytes and mature red cells. Biochim Biophys Acta 511:163–175

    PubMed  CAS  Google Scholar 

  • Brzezinska AK, Gebremedhin D, Chilian WM, Kalyanaraman B, Elliot SJ (2000) Peroxynitrite reversibly inhibits Ca2+-activated K+ channels in rat cerebral artery smooth muscle cells. Am J Physiol Heart Circ Physiol 278:1883–1890

    Google Scholar 

  • Budel S, Schuster A, Stergiopoulos N, Meister JJ, Beny JL (2001) Role of smooth muscle cells on endothelial cell cytosolic free calcium in porcine coronary arteries. Am J Heart Circ Physiol 281:1156–1162

    Google Scholar 

  • Bychkov R, Pieper K, Ried C, Milosheva M, Bychkov E, Luft FC, Haller H (1999) Hydrogen peroxide, potassium currents and membrane potential in human endothelial cells. Circulation 99:1719–1725

    PubMed  CAS  Google Scholar 

  • Bychkov R, Burnham MP, Richards GR, Edwards G, Weston AH, Félétou M, Vanhoutte PM (2002) Characterization of a charybdotoxin-sensitive intermediate conductance Ca2+-activated K+ channel in porcine coronary endothelium: relevance to EDHF. Br J Pharmacol 137:1346–1354

    PubMed  CAS  Google Scholar 

  • Calderone V (2002) Large-conductance, Ca2+-activated K+ channels: function, pharmacology and drugs. Curr Med Chem 9:1385–1395

    PubMed  CAS  Google Scholar 

  • Calderone V, Giorgi I, Livi O, Martinotti E, Mantuano E, Martelli A, Nardi A (2005) Benzoyl and/or benzyl substituted 1,2,3-triazoles as potassium channel activators. VIII. Eur J Med Chem 40:521–528

    PubMed  CAS  Google Scholar 

  • Calderone V, Martelli A, Testai L, Martinotti E, Breschi MC (2007) Functional contribution of the endothelial component to the vasorelaxing effect of resveratrol and NS 1619, activators of the large-conductance calcium-activated potassium channels. Naunyn Schmiedebergs Arch Pharmacol 375:73–80

    PubMed  CAS  Google Scholar 

  • Catacuzzeno L, Pisconti DA, Harper AA, Petris A, Franciolini F (2000) Characterization of the large-conductance Ca-activated K channel in myocytes of rat saphenous artery. Pflugers Arch 441:208–218

    PubMed  CAS  Google Scholar 

  • Chang T, Wu L, Wang R (2006) Altered expression of BK channel beta1 subunit in vascular tissues from spontaneously hypertensive rats. Am J Hypertens 19:678–685

    PubMed  CAS  Google Scholar 

  • Chiang HT, Wu SN (2001) Inhibition of large-conductance calcium-activated potassium channel by 2-methoxyestradiol in cultured vascular endothelial (HUV-EC-C) cells. J Membr Biol 182:203–212

    PubMed  CAS  Google Scholar 

  • Chow SE, Hshu YC, Wang JS, Chen JK (2007) Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages. J Appl Physiol 102:1520–1527

    PubMed  CAS  Google Scholar 

  • Coleman HA, Tare M, Parkington HC (2003) Endothelial potassium channels, endothelium-dependent hyperpolarization and the regulation of vascular tone in health and disease. Clin Exp Pharmacol Physiol 31:641–649

    Google Scholar 

  • Cox RH (2002) Changes in the expression and function of arterial potassium channels during hypertension. Vascul Pharmacol 38:13–23

    PubMed  CAS  Google Scholar 

  • Cox RH, Lozinskaya I, Dietz NJ (2001) Differences in K+ current components in mesenteric artery myocytes from WKY and SHR. Am J Hypertens 14:897–907

    PubMed  CAS  Google Scholar 

  • Dora KA, Sandow SL, Gallagher NT, Takano H, Rummery NM, Hill CE, Garland CJ (2003) Myoendothelial gap junctions may provide the pathway for EDHF in mouse mesenteric artery. J Vasc Res 40:480–490

    PubMed  Google Scholar 

  • Earley S, Heppner TJ, Nelson MT, Brayden JF (2005) TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ Res 97:1270–1279

    PubMed  CAS  Google Scholar 

  • Edwards G, Weston AH (1995) The role of potassium channels in excitable cells. Diabetes Res Clin Pract 28:57–66

    Google Scholar 

  • Edwards G, Niederste-Hollenberg A, Schneider J, Noack T, Weston AH (1994) Ion channel modulation by NS 1619, the putative BKCa channel opener, in vascular smooth muscle. Br J Pharmacol 113:1538–1547

    PubMed  CAS  Google Scholar 

  • Ekshyyan VP, Hebert VY, Khandelwal A, Dugas TR (2007) Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production. J Cardiovasc Pharmacol 50:83–93

    PubMed  CAS  Google Scholar 

  • Emerson GG, Segal SS (2000a) Endothelial coupling between endothelial cells and smooth muscle cells in hamster feed arteries: role in vasomotor control. Circ Res 87:474–479

    PubMed  CAS  Google Scholar 

  • Emerson GG, Segal SS (2000b) Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery. Circ Res 86:94–100

    PubMed  CAS  Google Scholar 

  • England SK, Wooldridge TA, Stekiel WJ, Rusch NJ (1993) Enhanced single-channel K+ current in arterial membranes from genetically hypertensive rats. Am J Physiol 264:1337–1345

    Google Scholar 

  • Essin K, Welling A, Hofmann F, Luft FC, Gollasch M, Moosmang S (2007) Indirect coupling between Cav1.2 channels and RyR to generate Ca2+ sparks in murine arterial smooth muscle cells. J Physiol 9 (E-publication ahead of print)

  • Félétou M, Vanhoutte PM (2000) Endothelium-dependent hyperpolarization of vascular smooth muscle cells. Acta Pharmacologia Sinica 21:1–18

    Google Scholar 

  • Félétou M, Vanhoutte PM (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26:1215–1225

    PubMed  Google Scholar 

  • Fernández-Fernández JM, Tomas M, Vazquez E, Orio P, Latorre R, Senti M, Marrugat J, Valverde MA (2004) Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension. J Clin Invest 113:1032–1039

    PubMed  Google Scholar 

  • Ferro A (2006) β-Adrenoceptor and potassium channels. Naunyn Schmiedebergs Arch Pharmacol 373:183–185

    CAS  Google Scholar 

  • Ferro A, Queen LR, Priest RM, Xu B, Ritter JM, Ward JP (1999) Activation of nitric oxide synthase by beta 2-adrenoceptors in human umbilical vein endothelium in vitro. Br J Pharmacol 126:1872–1880

    Google Scholar 

  • Ferro A, Coash M, Yamamoto T, Rob J, Ji Y, Queen L (2004) Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt. Br J Pharmacol 143:397–403

    PubMed  CAS  Google Scholar 

  • Frieden M, Graier WF (2000) Subplasmalemmal ryanodine-sensitive Ca2+ release contributes to Ca2+-dependent K+ channel activation in a human umbilical vein endothelial cell line. J Physiol 524:715–724

    PubMed  CAS  Google Scholar 

  • Fukao M, Mason HS, Britton FC, Kenyon JL, Horowitz B, Keef KD (1999) Cyclic GMP-dependent protein kinase activates cloned BKCa channel expression in mammalian cells by direct phosphorylation at serine 1072. J Biol Chem 274:10927–10935

    PubMed  CAS  Google Scholar 

  • Galvez A, Gimenez-Gallego G, Reuben JP, Roy-Contancin L, Feigenbaum P, Kaczorowski GJ, Garcia ML (1990) Purification and characterization of a unique, potent, peptidyl probe for the high conductance calcium-activated potassium channel from venom of the scorpion Buthus tamulus. J Biol Chem 265:11083–11090

    PubMed  CAS  Google Scholar 

  • Ghatta S, Nimmagadda D, Xu X, O’Rouke ST (2006) Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 110:103–116

    PubMed  CAS  Google Scholar 

  • Giangiacomo KM, Garcia ML, McManus OB (1992) Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle. Biochemistry 31:6719–6727

    PubMed  CAS  Google Scholar 

  • Gomes P, Srinivas SP, Vereecke J, Himpens B (2006) Gap junctional intercellular communication in bovine corneal endothelial cells. Exp Eye Res 83:1225–1237

    PubMed  CAS  Google Scholar 

  • Gorman ALF, Thomas MV (1980) Potassium conductance and internal calcium accumulation in a molluscan neurone. J Physiol 308:287–313

    PubMed  CAS  Google Scholar 

  • Gutterman DD, Miura H, Liu Y (2005) Redox modulation of vascular tone focus of potassium channel mechanisms of dilation. Arterioscler Thromb Vasc Biol 25:274–278

    Google Scholar 

  • Haburcák M, Wei L, Viana F, Peren J, Droogmans G, Nilius B (1997) Calcium-activated potassium channels in cultured human endothelial cells are not directly modulated by nitric oxide. Cell Calcium 21:291–300

    PubMed  Google Scholar 

  • Hotson JR, Prince DA (1980) A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J Neurophysiol 43:409–419

    PubMed  CAS  Google Scholar 

  • Hu S, Kim HS, Fink CA (1995) Differential effects of the BKCa channel openers NS004 and NS1608 in porcine coronary arterial cells. Eur J Pharmacol 294:357–360

    PubMed  CAS  Google Scholar 

  • Jackson WF (2005) Potassium channels in the peripheral microcirculation. Microcirculation 12:113–127

    PubMed  CAS  Google Scholar 

  • Jensen BS, Strøbæk D, Olesen SP, Christophersen P (2001) The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments? Curr Drug Targets 2:401–422

    PubMed  CAS  Google Scholar 

  • Kamouchi M, Droogmans G, Nilius B (1999) Membrane potential as a modulator of the free intracellular Ca2+ concentration in agonist-activated endothelial cells. Gen Physiol Biophys 18:199–208

    PubMed  CAS  Google Scholar 

  • Kestler HA, Janko S, Häussler U, Muche R, Hombach V, Höher M, Wiecha J (1998) A remark on the high-conductance calcium-activated potassium channel in human endothelial cells. Res Exp Med 198:133–143

    CAS  Google Scholar 

  • Kim KY, Cheon HG (2006) Antiangiogenic effect of rosiglitazone is mediated via peroxisome proliferators-activated receptor γ-activated maxi-K channel opening in human umbilical vein endothelial cells. J Biol Chem 281:13503–13512

    PubMed  CAS  Google Scholar 

  • Kim HI, Kim TH, Song JH (2005) Resveratrol inhibits Na+ currents in rat dorsal root ganglion neurons. Brain Res 1045:134–141

    PubMed  CAS  Google Scholar 

  • Knaus HG, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, Helms LM, Sanchez M, Giangiacomo K, Reuben JP, Smith AB 3rd, Kaczorowski GJ, Garcia ML (1994) Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry 33:5819–5828

    PubMed  CAS  Google Scholar 

  • Knaus HG, Eberhart A, Koch RO, Munujos P, Schmalhofer WA, Warmke JW, Kaczorowski GJ, Garcia ML (1995) Characterization of tissue-expressed alpha subunits of the high conductance Ca2+-activated K+ channel. J Biol Chem 270:22434–22439

    PubMed  CAS  Google Scholar 

  • Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JX (2001) Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol 280:970–979

    Google Scholar 

  • Krnjevíc K, Puil E, Werman R (1975) Evidence for Ca2+-activated K+ conductance in cat spinal motoneurons from intracellular EGTA injections. Can J Physiol Pharm 53:1214–1218

    Google Scholar 

  • Kuhlmann CR, Schafer M, Li F, Sawamura T, Tillmanns H, Waldecker B, Wiecha J (2003) Modulation of endothelial Ca2+-activated K+ channels by oxidized LDL and its contribution to endothelial proliferation. Cardiovasc Res 60:626–634

    PubMed  CAS  Google Scholar 

  • Kuhlmann CR, Gast C, Li Schäfer M, Tillmanns H, Waldecker B, Wiecha J (2004) Cerivastatin activates calcium-activated potassium channels and thereby modulates endothelial nitric oxide production and cell proliferation. J Am Soc Nephrol 15:868–875

    PubMed  Google Scholar 

  • Kuhlmann CR, Schaefer CA, Kosok C, Abdallah Y, Walther S, Lüdders DW, Neumann T, Tillmanns H, Schäfer C, Piper HM, Erdogan A (2005) Quercetin-induced induction of the NO/cGMP pathway depends on Ca2+-activated K+ channel-induced hyperpolarization-mediated Ca2+-entry into cultured human endothelial cells. Planta Med 71:520–524

    PubMed  CAS  Google Scholar 

  • Lang RJ, Harvey JR, McPhee GJ, Klemm MF (2000) Nitric oxide and thiol reagent modulation of Ca2+-activated K+ (BKCa) channels in myocytes of the guinea-pig taenia caeci. J Physiol 525:363–376

    PubMed  CAS  Google Scholar 

  • Latorre R, Brauchi S (2006) Large conductance Ca2+-activated K+ (BK) channel: activation by Ca2+ and voltage. Biol Res 39:385–401

    Article  PubMed  CAS  Google Scholar 

  • Ledoux J, Werner ME, Brayden JE, Nelson MT (2006) Calcium-activated potassium channels and the regulation of vascular tone. Physiol 21:69–78

    CAS  Google Scholar 

  • Lee CH, Poburko D, Kuo KH, Seow CY, van Breemen C (2002) Ca2+oscillation, gradients and homeostasis in vascular smooth muscle. Am J Physiol Heart Circ Physiol 282:1571–1583

    Google Scholar 

  • Li G, Cheung DW (1999) Effects of paxilline on K+ channels in rat mesenteric arterial cells. Eur J Pharmacol 372:103–107

    PubMed  CAS  Google Scholar 

  • Li HF, Chen SA, Wu SN (2000) Evidence for the stimulatory effect of resveratrol on Ca2+-activated K+ current in vascular endothelial cells. Cardiovasc Res 45:1035–1045

    PubMed  CAS  Google Scholar 

  • Liégeois JF, Mercier F, Graulich A, Graulich-Lorge F, Scuvée-Moreau J, Seutin V (2003) Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry. Curr Med Chem 10:625–647

    PubMed  Google Scholar 

  • Ling S, Woronuk G, Sy L, Lev S, Braun AP (2000) Enhanced activity of a large conductance, calcium-sensitive K+ channel in the presence of Src tyrosine kinase. J Biol Chem 275:30683–30689

    PubMed  CAS  Google Scholar 

  • Little TL, Xia J, Duling BR (1995) Dye tracers define differential endothelial and smooth muscle coupling patterns within the arteriolar wall. Circ Res 76:498–504

    PubMed  CAS  Google Scholar 

  • Liu Y, Gutterman DD (2002) Oxidative stress and potassium channel function. Clin Exp Pharmacol Physiol 29:305–311

    PubMed  CAS  Google Scholar 

  • Liu Y, Pleyte K, Knaus HG, Rusch NJ (1997) Increased expression of Ca2+-sensitive K+ channels in aorta of hypertensive rats. Hypertension 30:1403–1409

    PubMed  CAS  Google Scholar 

  • Liu Y, Hudetz AG, Knaus HG, Rusch NJ (1998) Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats evidence for their protection against cerebral vasospasm. Circ Res 82:729–737

    PubMed  CAS  Google Scholar 

  • Löhn M, Lauterbach B, Haller H, Pomgs O, Luft FC, Gollasch M (2001) β1-subunit of BK channels regulates arterial wall [Ca2+] and diameter in mouse cerebral arteries. J Appl Physiol 91:1350–1354

    PubMed  Google Scholar 

  • Lu R, Alioua A, Kumar Y, Eghbali M, Stefani E (2006) MaxiK channel partners: physiological impact. J Physiol 570:65–72

    PubMed  CAS  Google Scholar 

  • Luedders DW, Muenz BM, Li F, Rueckleben S, Tillmanns H, Waldecker B, Wiecha J, Erdogan A, Schaefer CA, Kuhlmann CR (2006) Role of cGMP in sildenafil-induced activation of endothelial Ca2+-activated K+ channels. J Cardiovasc Pharmacol 47:365–370

    PubMed  CAS  Google Scholar 

  • Ma R, Du J, Sours S, Ding M (2006) Store-operated Ca2+ channel in renal microcirculation and glomeruli. Exp Biol Med 231:145–153

    CAS  Google Scholar 

  • Martens JR, Gelband CH (1996) Alterations in rat interlobar artery membrane potential and K+ channels in genetic and nongenetic hypertension. Circ Res 79:295–301

    PubMed  CAS  Google Scholar 

  • Matsushita M, Tanaka Y, Koike K (2006) Studies on the mechanisms underlying beta-adrenoceptor-mediated relaxation of rat abdominal aorta. J Smooth Muscle Res 42:217–225

    PubMed  Google Scholar 

  • McGahon MK, Dash DP, Arora A, Wall N, Dawicki J, Simpson DA, Scholfield CN, McGeown JG, Curtis TM (2007) Diabetes downregulates large-conductance Ca2+-activated potassium beta1 channel subunit in retinal arteriolar smooth muscle. Circ Res 100:703–711

    PubMed  CAS  Google Scholar 

  • McKay MC, Dworetzky SI, Meanwell NA, Olesen SP, Reinhart PH, Levitan IB, Adelman JP, Gribkoff VK (1994) Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004. J Neurophysiol 71:1873–1882

    PubMed  CAS  Google Scholar 

  • McManus OB, Harris GH, Giangiacomo KM, Feigenbaum P, Reuben JP, Addy ME, Burka JF, Kaczorowski GJ, Garcia ML (1993) An activator of calcium-dependent potassium channels isolated from a medicinal herb. Biochemistry 32:6128–6133

    PubMed  CAS  Google Scholar 

  • McManus OB, Helms LM, Pallanck L, Ganetzky B, Swanson R, Leonard RJ (1995) Functional role of the beta subunit of high conductance calcium-activated potassium channels. Neuron 14:645–650

    PubMed  CAS  Google Scholar 

  • Meech RW (1972) Intracellular calcium injection causes increased potassium conductance in Aplysia nerve cells. Comp Biochem Physiol 42:493–499

    CAS  Google Scholar 

  • Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J (1999) Angiotensin-II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 100:899–902

    PubMed  CAS  Google Scholar 

  • Morikawa K, Matoba T, Kubota H, Hatanaka M, Fujiki T, Takahashi S, Takeshita A, Shimokawa H (2005) Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice. J Cardiovasc Pharmacol 45:485–490

    PubMed  CAS  Google Scholar 

  • Nagaoka T, Hein TW, Yoshida A, Kuo L (2007) Resveratrol, a component of red wine, elicits dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels. Invest Ophthalmol Vis Sci 48:4232–4239

    PubMed  Google Scholar 

  • Nara M, Dhulipala PD, Ji GJ, Kamasani UR, Wang YX, Matalon S, Kotlikoff MI (2000) Guanylyl cyclase stimulatory coupling to KCa channels. Am J Physiol Cell Physiol 279:1938–1945

    Google Scholar 

  • Navarro-Antolín J, Levitsky KL, Calderón E, Ordóñez A, López-Barneo J (2005) Decreased expression of maxi-K+ channel beta1-subunit and altered vasoregulation in hypoxia. Circulation 112:1309–1315

    PubMed  Google Scholar 

  • Nelson MT, Brayden JE (1993) Regulation of arterial tone by calcium-dependent K+ channels and ATP-sensitive K+ channels. Cardiovasc Drugs Ther 13:605–610

    Google Scholar 

  • Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, Lederer WJ (1995) Relaxation of arterial smooth muscle by calcium sparks. Science 270:633–637

    PubMed  CAS  Google Scholar 

  • Nimigean CM, Magleby KL (1999) The beta subunit increases the Ca2+ sensitivity of large conductance Ca2+-activated potassium channels by retaining the gating in the bursting states. J Gen Physiol 113:425–440

    PubMed  CAS  Google Scholar 

  • Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Phys Rev 81:1415–1459

    CAS  Google Scholar 

  • Nilius B, Viana F, Droogmans G (1997) Ion channels in vascular endothelium. Annu Rev Physiol 59:145–170

    PubMed  CAS  Google Scholar 

  • Nilius B, Droogmans G, Wondergem R (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10:5–15

    PubMed  CAS  Google Scholar 

  • Nilius B, Owsianik G, Voets T, Peteers JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217

    PubMed  CAS  Google Scholar 

  • Nishikawa T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9:343–353

    PubMed  CAS  Google Scholar 

  • O’Brien ER, Garvin MR, Dev R, Stewart DK, Hinohara T, Simpson JB, Schwartz SM (1994) Angiogenesis in human coronary atherosclerotic plaques. Am J Pathol 145:883–894

    PubMed  CAS  Google Scholar 

  • Olesen SP, Munch E, Moldt P, Drejer J (1994) Selective activation of Ca2+-dependent K+ channels by novel benzimidazolone. Eur J Pharmacol 251:53–59

    PubMed  CAS  Google Scholar 

  • Papassotiriou J, Köhler R, Prenen J, Krause H, Akbar M, Eggermont J, Paul M, Distler A, Nilius B, Hoyer J (2000) Endothelial K+ channel lacks the Ca2+ sensitivity regulating β-subunit. FASEB J 14:885–894

    PubMed  CAS  Google Scholar 

  • Parsaee H, McEwan JR, MacDermot J (1993) Bradykinin-induced release of PGI2 from aortic endothelial cell lines: responses mediated selectively by Ca2+ ions or a staurosporine-sensitive kinase. Br J Pharmacol 110:411–415

    PubMed  CAS  Google Scholar 

  • Reichenbach G, Momi S, Gresele P (2005) Nitric oxide and its antithrombotic action in the cardiovascular system. Curr Drug Targets Cardiovasc Haematol Disord 5:65–74

    PubMed  Google Scholar 

  • Richard S (2005) Vascular effects of calcium channel antagonists: new evidence. Drug 65:1–10

    CAS  Google Scholar 

  • Robertson BE, Schubert R, Hescheler J, Nelson MT (1993) cGMP-dependent protein kinase activates Ca2+-activated K+ channels in cerebral artery smooth muscle cells. Am J Physiol Cell Physiol 265:299–303

    Google Scholar 

  • Rusch NJ, De Lucena RG, Wooldridge TA, England SK, Cowley AW Jr (1992) A Ca2+-dependent K+ current is enhanced in arterial membranes of hypertensive rats. Hypertension 19:301–307

    PubMed  CAS  Google Scholar 

  • Rush JW, Quadrilatero J, Levy AS, Ford RJ (2007) Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels in aorta of spontaneously hypertensive rats. Exp Biol Med 232:814–822

    CAS  Google Scholar 

  • Rusko J, Tanzi F, van Breemen C, Adams DJ (1992) Calcium-activated potassium channels in native endothelial cells from rabbit aorta: conductance, calcium-sensitivity and block. J Physiol 455:601–621

    PubMed  CAS  Google Scholar 

  • Salkoff L, Butler A, Ferreira G, Santi C, Wei A (2006) High-conductance potassium channels of the SLO family. Nat Rev Neurosci 7:921–931

    PubMed  CAS  Google Scholar 

  • Sevov M, Elfineh L, Cavelier LB (2006) Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochem Biophys Res Commun 348:1047–1054

    PubMed  CAS  Google Scholar 

  • Seya Y, Fukuda T, Isobe K, Kawakami Y, Takekoshi K (2006) Effect of norepinephrine on RhoA, MAP kinase, proliferation and VEGF expression in human umbilical vein endothelial cells. Eur J Pharmacol 553:54–60

    PubMed  CAS  Google Scholar 

  • Snetkov VA, Aaronson PI, Ward JP, Knock GA, Robertson TP (2003) Capacitative calcium entry as a pulmonary specific vasoconstrictor mechanism in small muscular arteries of the rat. Br J Pharmacol 140:97–106

    PubMed  CAS  Google Scholar 

  • Sollini M, Frieden M, Bény JL (2002) Charybdotoxin-sensitive small conductance KCa channel activated by bradykinin and substance P in endothelial cells. Br J Pharmacol 136:1201–1209

    PubMed  CAS  Google Scholar 

  • Soto MA, González C, Lissi E, Vergara C, Latorre R (2002) Ca2+-activated K+ channel inhibition by reactive oxygen species. Am J Cell Physiol 282:461–471

    Google Scholar 

  • Stocker M (2004) Ca2+- activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci 5:758–770

    PubMed  CAS  Google Scholar 

  • Szkudelski T (2007) Resveratrol-induced inhibition of insulin secretion from rat pancreatic islets: evidence for pivotal role of metabolic disturbances. Am J Physiol Endocrinol Metab [E-publication ahead of print]

  • Tanaka Y, Meera P, Song M, Knaus HG, Toro L (1997) Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant alpha + beta subunit complexes. J Physiol 502:545–557

    PubMed  CAS  Google Scholar 

  • Tanaka Y, Koike K, Toro L (2004) MaxiK channel roles in blood vessel relaxations induced by endothelium-derived relaxing factors and their molecular mechanisms. J Smooth Muscle Res 40:125–153

    PubMed  Google Scholar 

  • Thirunavukkarasu M, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, Bagchi D, Das DK, Maulik N (2007) Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med 43:720–739

    PubMed  CAS  Google Scholar 

  • Tishkin SM, Rekalov VV, Ivanova IV, MoreLand RS, Soloviev AI (2007) Ionizing non-fatal whole-body irradiation inhibits Ca2+-dependent K+ channels in endothelial cells of rat coronary artery: possible contribution to depression of endothelium-dependent vascular relaxation. Int J Radiat Biol 83:161–169

    PubMed  CAS  Google Scholar 

  • Toro L, Wallner M, Meera P, Tanaka Y (1998) Maxi-K(Ca), a unique member of the voltage-gated K+ channel superfamily. News Physiol Sci 13:112–117

    PubMed  CAS  Google Scholar 

  • Ungvari Z, Csiszar A, Koller A (2002) Increases in endothelial Ca2+ activate KCa channels and elicit EDHF-type arteriolar dilation via gap junctions. Am J Physiol Heart Circ Physiol 282:1760–1767

    Google Scholar 

  • Van der Zypp A, Kang KB, Majewski H (2000) Age-related involvement of the endothelium in beta-adrenoceptor-mediated relaxation of rat aorta. Eur J Pharmacol 397:129–138

    PubMed  Google Scholar 

  • Wang XL, Ye D, Peterson TE, Cao S, Shah VH, Katusic ZS, Sieck GC, Lee HC (2005) Caveolae targeting and regulation or large conductance Ca2+-activated K+ channels in vascular endothelial cells. J Biol Chem 280:11656–11664

    PubMed  CAS  Google Scholar 

  • Wiecha J, Schlager B, Voisard R, Hannekum A, Mattfeldt T, Hombach V (1997) Ca2+-activated K+ channels in human smooth muscle cells of coronary atherosclerotic plaques and coronary media segments. Basic Res Cardiol 92:233–239

    PubMed  CAS  Google Scholar 

  • Wiecha J, Münz B, Wu Y, Noll T, Tillmanns H, Waldecker B (1998) Blockade of Ca2+-activated K+ channels inhibits proliferation of human endothelial cells induced by basic fibroblast growth factor. J Vasc Res 35:363–371

    PubMed  CAS  Google Scholar 

  • Wilson T, Knight TJ, Beitz DC, Lewis DS, Engen RL (1996) Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits. Life Sci 59:15–21

    Google Scholar 

  • Wu SN, Jan CR, Li HF, Chen SA (1999) Stimulation of large-conductance Ca2+-activated K+ channels by Evans blue in cultured endothelial cells of human umbilical veins. Biochem Biophys Res Commun 254:666–674

    PubMed  CAS  Google Scholar 

  • Xu X, Tsai TD, Wang J, Lee EW, Lee KS (1994) Modulation of three types of K+ currents in canine coronary artery smooth muscle cells by NS-004, or 1-(2′-hydroxy-5′-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone. J Pharmacol Exp Ther 271:362–369

    PubMed  CAS  Google Scholar 

  • Ye CL, Shen B, Ren XD, Luo RJ, Ding SY, Yan FM, Jiang JH (2004) An increase in opening of BKCa channels in smooth muscle cells in streptozotocin-induced diabetic mice. Acta Pharmacologia Sinica 25:744–750

    CAS  Google Scholar 

  • Yetik-Anacak C, Catravas JD (2006) Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascular Pharmacology 45:268–276

    PubMed  CAS  Google Scholar 

  • Zafar MU, Vilahur G, Choi BG, Ibanez B, Viles-Gonzalez JF, Salas E, Badimon JJ (2007) A novel anti-ischemic nitric oxide donor (LA419) reduces thrombogenesis in healthy human subjects. J Thromb Haemost 5:1195–1200

    PubMed  CAS  Google Scholar 

  • Zarai MM, Zhu N, Alioua A, Eghbali M, Stefani E, Toro L (2001) A novel MaxiK splice variant exhibits dominant-negative properties for surface expression. J Biol Chem 276:16232–16239

    Google Scholar 

  • Zmijewski JW, Moellering DR, Le Goffe C, Landar A, Ramachandran A, Darley-Usmar VM (2005) Oxidized LDL induces mitochondrially associated reactive oxygen/nitrogen species formation in endothelial cells. Am J Physiol Heart Circ Physiol 289:852–861

    Google Scholar 

  • Zou JG, Wang ZR, Huang YZ, Cao KJ, Wu JM (2003) Effect of red wine and wine polyphenol resveratrol on endothelial function in hypercholesterolemic rabbits. Int J Mol Med 11:317–320

    PubMed  CAS  Google Scholar 

  • Zsombok A, Schrofner S, Hermann A, Kerschbaum HH (2000) Nitric oxide increases excitability by decreasing a calcium activated potassium current in snail neurons. Neurosci Lett 295:85–88

    PubMed  CAS  Google Scholar 

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Acknowledgment

The authors thank the German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network) and the Fondation Leducq for research support and Ursula Ravens for critical reading of the manuscript.

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Eichhorn, B., Dobrev, D. Vascular large conductance calcium-activated potassium channels: Functional role and therapeutic potential. Naunyn-Schmied Arch Pharmacol 376, 145–155 (2007). https://doi.org/10.1007/s00210-007-0193-3

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