Skip to main content

Advertisement

SpringerLink
Log in

Pulmonary Circulation Under Pressure: Pathophysiological and Therapeutic Implications of BK Channel

  • Review Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

The large-conductance Ca2+-activated K+ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca+2 concentration, and chronic hypoxia, resulting in massive K+ efflux, membrane hyperpolarization, decreased L-type Ca+2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

Not applicable.

Code Availability

Not applicable.

References 

  1. Swan HJC, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med. Massachusetts Med Soc. 1970;283:447–51.

    CAS  Google Scholar 

  2. Follath F, Burkart F, Schweizer W. Drug-induced pulmonary hypertension? Br Med. J Br Med J Publ Group. 1971;1:265–6.

    Article  CAS  Google Scholar 

  3. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:1801913.

  4. Gidwani S, Nair A. The burden of pulmonary hypertension in resource-limited settings. Glob Heart World Heart Federation (Geneva). 2014;9:297–310.

    Google Scholar 

  5. Galiè N, Humbert M, Vachiéry J-L, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J Oxford University Press. 2015;37:67–119.

    Google Scholar 

  6. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–63.

    Article  PubMed  Google Scholar 

  7. Petitpretz P, Brenot F, Azarian R, et al. Pulmonary hypertension in patients with human immunodeficiency virus infection Comparison with primary pulmonary hypertension. Circulation. 1994;89:2722–7.

    Article  CAS  PubMed  Google Scholar 

  8. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J European Respiratory Society. 2005;25:244–9.

    Article  CAS  Google Scholar 

  9. Toro L, Amador M, Stefani E. ANG II inhibits calcium-activated potassium channels from coronary smooth muscle in lipid bilayers. Am J Physiol - Hear Circ Physiol. 1990;258:H912–H915.

  10. Toro L, Vaca L, Stefani E. Calcium-activated potassium channels from coronary smooth muscle reconstituted in lipid bilayers. Am J Physiol - Hear Circ Physiol. 1991;260:H1779–H1789.

  11. Revermann M, Neofitidou S, Kirschning T, Schloss M, Brandes RP, Hofstetter C. Inhalation of the BKCa -opener NS1619 attenuates right ventricular pressure and improves oxygenation in the rat monocrotaline model of pulmonary hypertension. Fukai T, editor. PLoS One. 2014;9:e86636 Public Library of Science.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ferraz AP, Seara FAC, Baptista EF, et al. BKCa Channel activation attenuates the pathophysiological progression of monocrotaline-induced pulmonary arterial hypertension in Wistar rats. Cardiovasc Drugs Ther Springer. 2021;35:719–32.

    Article  CAS  Google Scholar 

  13. Harvey W. On the motion of the heart and blood in animals. 1st ed. Editora Unesp; 2013.

  14. Kilner PJ, Balossino R, Dubini G, et al. Pulmonary regurgitation: the effects of varying pulmonary artery compliance, and of increased resistance proximal or distal to the compliance. Int J Cardiol Elsevier. 2009;133:157–66.

    Article  Google Scholar 

  15. Lankhaar JW, Westerhof N, Faes TJC, et al. Quantification of right ventricular afterload in patients with and without pulmonary hypertension. Am J Physiol - Hear Circ Physiol American Physiological Society. 2006;291:1731–7.

    Article  Google Scholar 

  16. Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. Am College Cardiol FoundWashington DC. 2004;43:S5-12.

    Article  Google Scholar 

  17. Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th world symposium on pulmonary hypertension. Eur Respir J. 2019;53:1802148.

  18. Ryan JJ, Rich JD, Thiruvoipati T, Swamy R, Kim GH, Rich S. Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. Am Heart J Mosby. 2012;163:589–94.

    Article  Google Scholar 

  19. Tampakakis E, Shah SJ, Borlaug BA, et al. Pulmonary effective arterial elastance as a measure of right ventricular afterload and its prognostic value in pulmonary hypertension due to left heart disease. Circ Hear Fail. 2018;11:e004436.

  20. Tampakakis E, Leary PJ, Selby VN, et al. The diastolic pulmonary gradient does not predict survival in patients with pulmonary hypertension due to left heart disease. JACC Hear Fail. Am College Cardiol Found Washington DC. 2015;3:9–16.

    Google Scholar 

  21. Rain S, Handoko ML, Trip P, et al. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation. Lippincott Williams & Wilkins Hagerstown, MD 2013;128:2016–25

  22. Stojnic BB, Brecker SJD, Xiao HB, Helmy SM, Mbaissouroum M, Gibson DG. Left ventricular filling characteristics in pulmonary hypertension: a new mode of ventricular interaction. Heart. 1992;68:16–20 BMJ Publishing Group Ltd.

    Article  CAS  Google Scholar 

  23. Mak S, Witte KK, Al-Hesayen A, Granton JJ, Parker JD. Cardiac sympathetic activation in patients with pulmonary arterial hypertension. Am Physiol Soc Bethesda MD. 2012;302:1153–7.

    Google Scholar 

  24. Zhang YX, Li JF, Yang YH, et al. Renin-angiotensin system regulates pulmonary arterial smooth muscle cell migration in chronic thromboembolic pulmonary hypertension. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2018;314:L276-86.

    Google Scholar 

  25. Shang X, Xiao S, Dong N, et al. Assessing right ventricular function in pulmonary hypertension patients and the correlation with the New York Heart Association (NYHA) classification Oncotarget. Impact J LLC. 2017;8:90421.

    Google Scholar 

  26. Kaneko FT, Arroliga AC, Dweik RA, et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med American Thoracic SocietyNew York, NY. 1998;158:917–23.

    Article  CAS  Google Scholar 

  27. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. Massachusetts Med Soc. 2010;327:70–5.

    Google Scholar 

  28. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circ Lippincott Williams Wilkins. 1992;85:504–9.

    CAS  Google Scholar 

  29. Fayyaz AU, Edwards WD, Maleszewski JJ, et al. Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction. Circ Lippincott Williams Wilkins. 2018;137:1796–810.

    Google Scholar 

  30. Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-β1 and bone morphogenetic proteins. Circ Lippincott Williams Wilkins. 2001;104:790–5.

    CAS  Google Scholar 

  31. Archer SL, Huang JMC, Reeve HL, et al. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res Lippincott Williams Wilkins. 1996;78:431–42.

    CAS  Google Scholar 

  32. Peinado VI, París R, Ramírez J, Roca J, Rodriguez-Roisin R, Barberà JA. Expression of BKCa channels in human pulmonary arteries: relationship with remodeling and hypoxic pulmonary vasoconstriction. Vascul Pharmacol Elsevier. 2008;49:178–84.

    Article  CAS  Google Scholar 

  33. Pallotta BS, Magleby KL, Barrett JN. Single channel recordings of Ca2+-activated K+ currents in rat muscle cell culture. Nature Nature Publ Group. 1981;293:471–4.

    CAS  Google Scholar 

  34. Benham CD, Bolton TB, Lang RJ, Takewaki T. Calcium-activated potassium channels in single smooth muscle cells of rabbit jejunum and guinea-pig mesenteric artery. J Physiol. 1986;371:45–67 John Wiley & Sons, Ltd.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Inoue R, Kitamura K, Kuriyama H. Two Ca-dependent K-channels classified by the application of tetraethylammonium distribute to smooth muscle membranes of the rabbit portal vein. Pflügers Arch Eur J Physiol Springer. 1985;405:173–9.

    Article  CAS  Google Scholar 

  36. Marty A. Ca2+-dependent K+ channels with large unitary conductance. Trends Neurosci. 1983;262–5

  37. Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L. mSlo, a complex mouse gene encoding “maxi” calcium-activated potassium channels. Science Am Assoc Adv Sci. 1993;261:221–4.

    CAS  Google Scholar 

  38. Leo MD, Bannister JP, Narayanan D, et al. Dynamic regulation of β1 subunit trafficking controls vascular contractility. Proc Natl Acad Sci U S A National Academy of Sciences. 2014;111:2361–6.

    Article  CAS  Google Scholar 

  39. Meera P, Wallner M, Song M, Toro L. Large conductance voltage- and calcium-dependent K+ channel, a distinct member of voltage-dependent ion channels with seven N-terminal transmembrane segments (SO-S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus. Proc Natl Acad Sci U S A National Academy of Sciences. 1997;94:14066–71.

    Article  CAS  Google Scholar 

  40. Wallner M, Meera P, Toro L. Determinant for β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: an additional transmembrane region at the N terminus. Proc Natl Acad Sci U S A National Academy of Sciences. 1996;93:14922–7.

    Article  CAS  Google Scholar 

  41. Tao X, Hite RK, MacKinnon R. Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel. Nature. 2017;541:46–51 Nature Publishing Group.

    Article  CAS  PubMed  Google Scholar 

  42. Soom M, Gessner G, Heuer H, Hoshi T, Heinemann SH. A mutually exclusive alternative exon of slo1 codes for a neuronal BK channel with altered function. Channels. 2008;2:278–82 Taylor & Francis.

    Article  PubMed  Google Scholar 

  43. Brenner R, Jegla TJ, Wickenden A, Liu Y, Aldrich RW. Cloning and functional characterization of novel large conductance calcium-activated potassium channel β subunits, hKCNMB3 and hKCNMB4. J Biol Chem Elsevier. 2000;275:6453–61.

    Article  CAS  Google Scholar 

  44. Hu S, Labuda MZ, Pandolfo M, Goss GG, McDermid HE, Ali DW. Variants of the KCNMB3 regulatory subunit of maxi BK channels affect channel inactivation. Physiol Genomics. 2004;15:191–8 American Physiological Society.

    Article  Google Scholar 

  45. Yan J, Aldrich RW. BK potassium channel modulation by leucine-rich repeat-containing proteins. Proc Natl Acad Sci U S A. 2012;109:7917–22 National Academy of Sciences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Evanson KW, Bannister JP, Leo MD, Jaggar JH. LRRC26 is a functional BK channel auxiliary γ subunit in arterial smooth muscle cells. Circ Res. 2014;115:423–31 Lippincott Williams and Wilkins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang H, Zhang G, Cui J. BK channels: multiple sensors, one activation gate. Front Physiol. 2015;6:29 Frontiers Media S.A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stefani E, Ottolia M, Noceti F, et al. Voltage-controlled gating in a large conductance Ca2+-sensitive K+ channel (hslo). Proc Natl Acad Sci U S A. 1997;94:5427–31 National Academy of Sciences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Siemen D, Loupatatzis C, Borecky J, Gulbins E, Lang F. Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line. Biochem Biophys Res Commun Academic Press. 1999;257:549–54.

    Article  CAS  Google Scholar 

  50. Xu W, Liu Y, Wang S, et al. Cytoprotective role of Ca2+-activated K+ channels in the cardiac inner mitochondrial membrane. Science. 2002;298:1029–33 (American Association for the Advancement of Science).

    Article  CAS  PubMed  Google Scholar 

  51. Cheng Y, Gulbins E, Siemen D. Activation of the permeability transition pore by Bax via inhibition of the mitochondrial BK channel. Cell Physiol Biochem S Karger AG. 2011;27:191–200.

    Article  CAS  Google Scholar 

  52. Bednarczyk P, Koziel A, Jarmuszkiewicz W, Szewczyk A. Large-conductance Ca2+-activated potassium channel in mitochondria of endothelial EA.hy926 cells. Am J Physiol - Hear Circ Physiol American Physiological Society Bethesda, MD. 2013;304:1415–27.

    Article  Google Scholar 

  53. Singh H, Lu R, Bopassa JC, Meredith AL, Stefani E, Toro L. MitoBKCa is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location. Proc Natl Acad Sci U S A National Academy of Sciences. 2013;110:10836–41.

    Article  CAS  Google Scholar 

  54. Loot AE, Moneke I, Keserü B, et al. 11, 12-EET Stimulates the association of BK channel α and β1 subunits in mitochondria to induce pulmonary vasoconstriction. PLoS One Public Library of Science. 2012;7:e46065.

    Article  CAS  Google Scholar 

  55. Soltysinska E, Bentzen BH, Barthmes M, et al. KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury. PLoS One Public Library of Science. 2014;9:e103402.

    Article  Google Scholar 

  56. Yuan XJ, Wang J, Juhaszova M, Golovina VA, Rubin LJ. Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells. Am J Physiol - Lung Cell Mol Physiol. 1998;274

  57. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol - Cell Physiol. 1995;268:C799–C822.

  58. Wamhoff BR, Bowles DK, McDonald OG, et al. L-type voltage-gated Ca2+ channels modulate expression of smooth muscle differentiation marker genes via a Rho kinase/myocardin/SRF–dependent mechanism. Circ Res Lippincott Williams & Wilkins. 2004;95:406–14.

    CAS  Google Scholar 

  59. Saitoh M, Ishikawa T, Matsushima S, Naka M, Hidaka H. Selective inhibition of catalytic activity of smooth muscle myosin light chain kinase. J Biol Chem Elsevier. 1987;262:7796–801.

    Article  CAS  Google Scholar 

  60. Kojima M, Dohi Y, Sato K. Ryanodine-induced contraction in femoral artery from spontaneously hypertensive rats. Eur J Pharmacol Elsevier. 1994;254:159–65.

    Article  CAS  Google Scholar 

  61. Alexander RW, Brock TA, Gimbrone MA, Rittenhouse SE. Angiotensin increases inositol trisphosphate and calcium in vascular smooth muscle. Hypertension Ovid Technologies (Wolters Kluwer Health). 1985;7:447–51.

    CAS  Google Scholar 

  62. Etter EF, Eto M, Wardle RL, Brautigan DL, Murphy RA. Activation of myosin light chain phosphatase in intact arterial smooth muscle during nitric oxide-induced relaxation. J Biol Chem Elsevier. 2001;276:34681–5.

    Article  CAS  Google Scholar 

  63. Rembold CM, Murphy RA. Myoplasmic calcium, myosin phosphorylation, and regulation of the crossbridge cycle in swine arterial smooth muscle. Circ Res. 1986;58:803–15.

    Article  CAS  PubMed  Google Scholar 

  64. Tanaka Y, Koike K, Toro L. MaxiK channel roles in blood vessel relaxations induced by endothelium-derived relaxing factors and their molecular mechanisms. J. Smooth Muscle Res. Japan Society of Smooth Muscle Research; 2004; 125–53

  65. Drab M, Verkade P, Elger M, et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science American Association for the Advancement of Science. 2001;293:2449–52.

    Article  CAS  Google Scholar 

  66. Pritchard HAT, Griffin CS, Yamasaki E, et al. Nanoscale coupling of junctophilin-2 and ryanodine receptors regulates vascular smooth muscle cell contractility. Proc Natl Acad Sci U S A National Academy of Sciences. 2019;116:21874–81.

    Article  CAS  Google Scholar 

  67. Nelson MT, Cheng H, Rubart M, et al. Relaxation of arterial smooth muscle by calcium sparks. Science American Association for the Advancement of Science. 1995;270:633–7.

    Article  CAS  Google Scholar 

  68. Jaggar JH, Porter VA, Jonathan Lederer W, Nelson MT. Calcium sparks in smooth muscle. Am. J. Physiol. - Cell Physiol. American Physiological Society; 2000; 235–56

  69. Dennis Leo M, Zhai X, Muralidharan P, et al. Membrane depolarization activates BK channels through ROCK-mediated β1 subunit surface trafficking to limit vasoconstriction. Sci Signal. American Association for the Advancement of Science; 2017;10

  70. Kirber MT, Ordway RW, Clapp LH, Walsh JV. Singer JJ. Both membrane stretch and fatty acids directly activate large conductance Ca2+-activated K+ channels in vascular smooth muscle cells. FEBS Lett John Wiley & Sons, Ltd. 1992;297:24–8.

    Article  CAS  Google Scholar 

  71. Piao L, Ho WK, Earm YE. Actin filaments regulate the stretch sensitivity of large-conductance, Ca2+-activated K+ channels in coronary artery smooth muscle cells. Pflugers Arch Eur J Physiol Springer. 2003;446:523–8.

    Article  CAS  Google Scholar 

  72. Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol - Cell Physiol. American Physiological Society Bethesda, MD; 1992; 262

  73. Resnik E, Herron J, Fu R, Ivy DD, Cornfield DN. Oxygen tension modulates the expression of pulmonary vascular BK Ca channel α- and β-subunits. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2006;290:761–8.

    Article  Google Scholar 

  74. Barnes EA, Lee L, Barnes SL, Brenner R, Alvira CM, Cornfield DN. ß1-Subunit of the calcium-sensitive potassium channel modulates the pulmonary vascular smooth muscle cell response to hypoxia. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2018;315:265–75.

    Article  Google Scholar 

  75. Marino M, Bény JL, Peyter AC, Diaceri G, Tolsa JF. Perinatal hypoxia enhances cyclic adenosine monophosphate-mediated BK Ca channel activation in adult murine pulmonary artery. J Cardiovasc Pharmacol. 2011;57:154–65.

    Article  CAS  PubMed  Google Scholar 

  76. Gu XQ, Pamenter ME, Siemen D, Sun X, Haddad GG. Mitochondrial but not plasmalemmal BK channels are hypoxia-sensitive in human glioma. Glia John Wiley & Sons, Ltd. 2014;62:504–13.

    Google Scholar 

  77. Moral-Sanz J, Lewis SA, MacMillan S, et al. The LKB1–AMPK-1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria. Sci Signal American Association for the Advancement of Science. 2018;11:296.

    Google Scholar 

  78. Vandier C, Bonnet P. Role of Ca2+-sensitive K+ channels in the remission phase of pulmonary hypertension in chronic obstructive pulmonary diseases. 2003;60:326–36

  79. Babicheva A, Ayon RJ, Zhao T, et al. MicroRNA-mediated downregulation of K+ channels in pulmonary arterial hypertension. Am J Physiol - Lung Cell Mol Physiol. 2020;318:L10-26.

    Article  CAS  PubMed  Google Scholar 

  80. Brenner R, Peréz GJ, Bonev AD, et al. Vasoregulation by the β1 subunit of the calcium-activated potassium channel. Nat Publ Group. 2000;407:870–6.

    CAS  Google Scholar 

  81. Varshney R, Ali Q, Wu C, Sun Z. Monocrotaline-induced pulmonary hypertension involves downregulation of antiaging protein klotho and eNOS activity. Hypertension Lippincott Williams and Wilkins. 2016;68:1255–63.

    CAS  Google Scholar 

  82. Murata T, Sato K, Hori M, Ozaki H, Karaki H. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem Elsevier. 2002;277:44085–92.

    Article  CAS  Google Scholar 

  83. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature Nature Publishing Group. 1988;333:664–6.

    CAS  Google Scholar 

  84. Amezcua JL, Dusting GJ, Palmer RMJ, Moncada S. Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol Wiley-Blackwell. 1988;95:830–4.

    Article  CAS  Google Scholar 

  85. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences. 1997;74:3203–7.

    Article  Google Scholar 

  86. Cohen RA, Weisbrod RM, Gericke M, Yaghoubi M, Bierl C, Bolotina VM. Mechanism of nitric oxide-induced vasodilatation: refilling of intracellular stores by sarcoplasmic reticulum Ca2+ ATPase and inhibition of store-operated Ca2+ influx. Circ Res Lippincott Williams & Wilkins. 1999;84:210–9.

    CAS  Google Scholar 

  87. Ferrer M, Marín J, Encabo A, Alonso MJ, Balfagón G. Role of K+ channels and sodium pump in the vasodilation induced by acetylcholine, nitric oxide, and cyclic GMP in the rabbit aorta. Gen Pharmacol Pergamon. 1999;33:35–41.

    Article  CAS  Google Scholar 

  88. Gagov H, Gribkova IV, Serebryakov VN, Schubert R. Sodium nitroprusside-induced activation of vascular smooth muscle BK channels is mediated by PKG rather than by a direct interaction with NO. Int J Mol Sci Multidisciplinary Digital Publishing Institute. 2022;23:2798.

    CAS  Google Scholar 

  89. Alioua A, Tanaka Y, Wallner M, et al. The large conductance, voltage-dependent, and calcium-sensitive K+ channel, Hslo, is a target of cGMP-dependent protein kinase phosphorylation in vivo. J Biol Chem Elsevier. 1998;273:32950–6.

    Article  CAS  Google Scholar 

  90. Fukao M, Mason HS, Britton FC, Kenyon JL, Horowitz B, Keef KD. Cyclic GMP-dependent protein kinase activates cloned BK(Ca) channels expressed in mammalian cells by direct phosphorylation at serine 1072. J Biol Chem Elsevier. 1999;274:10927–35.

    Article  CAS  Google Scholar 

  91. Nara M, Dhulipala PDK, Ji GJ, et al. Guanylyl cyclase stimulatory coupling to K(Ca) channels. Am J Physiol - Cell PhysiolAmerican Physiological Society; 2000; 279

  92. Hu S, Kim HS, Jeng AY. Dual action of endothelin-1 on the Ca2+-activated K+ channel in smooth muscle cells of porcine coronary artery. Eur J Pharmacol Elsevier. 1991;194:31–6.

    Article  CAS  Google Scholar 

  93. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am Thoracic Soc New York, NY. 2012;159:1925–32.

    Google Scholar 

  94. Dusting GJ, Moncada S, Vane JR. Prostacyclin (PGX) is the endogeneous metabolite responsible for relaxation of coronary arteries induced by arachidonic acid. Prostaglandins Elsevier. 1977;13:3–15.

    Article  CAS  Google Scholar 

  95. Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. Chest Elsevier. 1989;96:784–9.

    Article  CAS  Google Scholar 

  96. Phillips PG, Long L, Wilkins MR, Morrell NW. cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2005;288:103–15.

    Article  Google Scholar 

  97. Barman SA, Zhu S, Han G, White RE. cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2003;284:1004–11.

    Article  Google Scholar 

  98. Zhu S, White RE, Barman SA. Original Research: Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle. Ther Adv Respir Dis SAGE PublicationsSage UK: London, England. 2008;2:119–27.

    Article  Google Scholar 

  99. Schubert R, Serebryakov VN, Engel H, Hopp HH. Iloprost activates KCa channels of vascular smooth muscle cells: role of cAMP-dependent protein kinas. American Physiological Society Bethesda, MD 1996; 271

  100. Schubert R, Serebryakov VN, Mewes H, Hopp HH. Iloprost dilates rat small arteries: role of K(ATP)- and K(Ca)-channel activation by cAMP-dependent protein kinase. American Physiological Society Bethesda, MD ; 1997; 272

  101. Toro L, Wallner M, Meera P, Tanaka Y. Maxi-KCa, a unique member of the voltage-gated K channel superfamily. News Physiol Sci American Physiological Society. 1998;13:112–7.

    CAS  Google Scholar 

  102. Porter VA, Bonev AD, Knot HJ, et al. Frequency modulation of Ca2+ sparks is involved in regulation of arterial diameter by cyclic nucleotides. Am J Physiol - Cell Physiol. American Physiological Society; 1998; 274

  103. Scornik FS, Codina J, Birnbaumer L, Toro L. Modulation of coronary smooth muscle K(Ca) channels by G(s)α independent of phosphorylation by protein kinase A. Am J Physiol - Hear Circ Physiol. American Physiological Society Bethesda, MD; 1993; 265

  104. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension;328:1732–9

  105. Orte C, Polak JM, Haworth SG, Yacoub MH, Morrell NW. Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension. J Pathol. 2000;192:379–84.

    Article  CAS  PubMed  Google Scholar 

  106. Barman SA. Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C. Am J Physiol - Lung Cell Mol Physiol. American Physiological Society; 2007;293:472–9;

  107. Scornik FS, Toro L. U46619, a thromboxane A2 agonist, inhibits K(Ca) channel activity from pig coronary artery. Am J Physiol - Cell Physiol. American Physiological Society Bethesda, MD; 1992; 262

  108. Li M, Zhang Z, Koh H, et al. The β1-subunit of the MaxiK channel associates with the thromboxane A2 receptor and reduces thromboxane A2 functional effects. J Biol Chem Elsevier. 2013;288:3668–77.

    Article  CAS  Google Scholar 

  109. Zhai X, Leo MD, Jaggar JH. Endothelin-1 stimulates vasoconstriction through Rab11A serine 177 phosphorylation. Circ Res Lippincott Williams and Wilkins. 2017;121:650–61.

    CAS  Google Scholar 

  110. Dennis Leo M, Bulley S, Bannister JP, Kuruvilla KP, Narayanan D, Jaggar JH. Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction. Am J Physiol - Cell Physiol American Physiological Society. 2015;309:C392-402.

    Article  Google Scholar 

  111. Barman SA, Zhu S, White RE. PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2004;286:1275–81.

    Article  Google Scholar 

  112. Li M, Tanaka Y, Alioua A, et al. Thromboxane A2 receptor and MaxiK-channel intimate interaction supports channel trans-inhibition independent of G-protein activation. Proc Natl Acad Sci U S A National Academy of Sciences. 2010;107:19096–101.

    Article  CAS  Google Scholar 

  113. Brenner R, Chen QH, Vilaythong A, Toney GM, Noebels JL, Aldrich RW. BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nat Neurosci 2005 812 Nature Publishing Group. 2005;8:1752–9.

    CAS  Google Scholar 

  114. Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet Nature Publishing Group. 2005;37:733–8.

    Article  CAS  Google Scholar 

  115. Gueutin V, Vallet M, Jayat M, et al. Renal β-intercalated cells maintain body fluid and electrolyte balance. J Clin Invest American Society for Clinical Investigation. 2013;123:4219–31.

    Article  CAS  Google Scholar 

  116. Valverde MA, Rojas P, Amigo J, et al. Acute activation of Maxi-K channels (hSlo) by estradiol binding to the β subunit. Science American Association for the Advancement of Science. 1999;285:1929–31.

    Article  CAS  Google Scholar 

  117. Tofovic SP, Salah EM, Mady HH, Jackson EK, Melhem MF. Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. 2005;46:430–7.

    Article  CAS  PubMed  Google Scholar 

  118. Frump AL, Albrecht M, Yakubov B, et al. 17β-estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin. J Clin Invest. American Society for Clinical Investigation 2021; 131

  119. Farrukh IS, Peng W, Orlinska U, Hoidal JR. Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca2+-activated K+-channel opener. Am J Physiol - Lung Cell Mol Physiol. American Physiological Society; 1998; 274

  120. Dumas De La Roque E, Quignard JF, Ducret T, et al. Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants. Pediatr Res Pediatr Res. 2013;74:163–9.

    Article  CAS  PubMed  Google Scholar 

  121. King JT, Lovell PV, Rishniw M, Kotlikoff MI, Zeeman ML, McCobb DP. β2 and β4 subunits of BK channels confer differential sensitivity to acute modulation by steroid hormones. J Neurophysiol American Physiological Society. 2006;95:2878–88.

    Article  CAS  Google Scholar 

  122. Dumas de La Roque E, Savineau JP, Metivier AC, et al. Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study. Ann Endocrinol (Paris). Elsevier Masson SAS; 2012;73:20–5

  123. Walsh TP, Baird GL, Atalay MK, et al. Experimental design of the effects of dehydroepiandrosterone in pulmonary hypertension (EDIPHY) trial. Pulm Circ Wiley-Blackwell. 2021;11:1–9.

    Article  CAS  Google Scholar 

  124. Giangiacomo KM, Kamassah A, Harris G, Mcmanus OB. Mechanism of maxi-K channel activation by dehydrosoyasaponin-I. J Gen Physiol The Rockefeller University Press. 1998;112:485–501.

    Article  CAS  Google Scholar 

  125. Huai X, Sun Y, Sun X, et al. The effect of docosahexaenoic acid on predicting the survival of patients with idiopathic pulmonary arterial hypertension. Ann Transl Med AME Publications. 2021;9:995–995.

    Article  CAS  Google Scholar 

  126. Moriyama H, Endo J, Kataoka M, et al. Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling. Nat Commun Nature Publishing Group. 2022;13:1–13.

    Google Scholar 

  127. Hoshi T, Wissuwa B, Tian Y, et al. Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+ channels. Proc Natl Acad Sci U S A. 2013;110:4816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hoshi T, Tian Y, Xu R, Heinemann SH, Hou S. Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA. Proc Natl Acad Sci U S A. 2013;110:4822–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nagaraj C, Tang B, Nagy BM, et al. Docosahexaenoic acid causes rapid pulmonary arterial relaxation via KCa channel-mediated hyperpolarisation in pulmonary hypertension. Eur Respir J. 2016;48:1127–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen R, Zhong W, Shao C, et al. Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2018;314:L243-55.

    Google Scholar 

  131. Zhong Y, Catheline D, Houeijeh A, et al. Maternal omega-3 PUFA supplementation prevents hyperoxia-induced pulmonary hypertension in the offspring. Am J Physiol - Lung Cell Mol Physiol American Physiological Society. 2018;315:L116-32.

    Article  CAS  Google Scholar 

  132. Zhang X, Ritonja JA, Zhou N, Chen BE, Li X. Omega-3 polyunsaturated fatty acids intake and blood pressure: a dose-response meta-analysis of randomized controlled trials. J. Am. Heart Assoc. American Heart Association Inc.; 2022; 25071

  133. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation. Lippincott Williams & Wilkins Hagerstown, MD; 2019; E673–91

  134. Olesen. Benzimidazole derivatives, their preparation and use. US Patent No 5200422A. 1993. https://patents.google.com/patent/US5200422A/en. Accessed 20 Feb 2023.

  135. Olesen S, Moldt P, Pedersen O. Urea and amide derivatives and their use in the control of cell membrane potassium channels (US5696138A). Int Patent Appl. 1994;121. https://patents.google.com/patent/US5696138A/en. Accessed 20 Feb 2023.

  136. Olesen SP, Munch E, Wätjen F, Drejer J. NS 004—an activator of Ca2+–dependent K+ channels in cerebellar granule cells. NeuroReport. 1994;5:1001–4.

    Article  CAS  PubMed  Google Scholar 

  137. Macmillan S, Sheridan RD, Chilvers ER, Patmore L. A comparison of the effects of SCA40, NS 004 and NS 1619 on large conductance Ca2+-activated K+ channels in bovine tracheal smooth muscle cells in culture. Br J Pharmacol Wiley-Blackwell. 1995;116:1656–60.

    Article  CAS  Google Scholar 

  138. Hu S, Kim HS, Fink CA, Dirishm P. Differential effects of the BKca channel openers NS004 and NS1608 in porcine coronary arterial cells. Eur J Pharmacol Elsevier. 1995;294:6–9.

    Google Scholar 

  139. Hu S, Kim HS. On the mechanism of the differential effects of NS004 and 1608 in smooth muscle cells from guinea pig bladder. Eur J Pharmacol Elsevier. 1996;318:461–8.

    Article  CAS  Google Scholar 

  140. Vandier C, Bonnet P. Synergistic action of NS-004 and internal Ca2+ concentration in modulating pulmonary artery K+ channels. Eur J Pharmacol. 1996;295:53–60.

    Article  CAS  PubMed  Google Scholar 

  141. Strøbæk D, Christophersen P, Holm NR, et al. Modulation of the Ca2+-dependent K+ channel, hslo, by the substituted diphenylurea NS 1608, paxilline and internal Ca2+. Neuropharmacology Pergamon. 1996;35:903–14.

    Article  Google Scholar 

  142. Olesen S-PP, Munch E, Moldt P, Drejer J. Selective activation of Ca2+ -dependent K+ channels by novel benzimidazolone. Eur J Pharmacol Elsevier. 1994;251:53–9.

    Article  CAS  Google Scholar 

  143. Edwards G, Niederste-Hollenberg A, Schneider J, Noack T, Weston AH. Ion channel modulation by NS 1619, the putative BKCa channel opener, in vascular smooth muscle. Br J Pharmacol John Wiley & Sons, Ltd. 1994;113:1538–47.

    CAS  Google Scholar 

  144. Wrzosek A. The potassium channel opener NS1619 modulates calcium homeostasis in muscle cells by inhibiting SERCA. Cell Calcium Churchill Livingstone. 2014;56:14–24.

    Article  CAS  Google Scholar 

  145. McCullough DJ, Vang A, Choudhary G. NS1619-induced vasodilation is enhanced and differentially mediated in chronically hypoxic lungs. Lung Springer Science and Business Media, LLC. 2014;192:811–7.

    CAS  Google Scholar 

  146. Ivy DD, Doran AK, Smith KJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol Foundation Washington, D.C. 2008;51:161–9.

  147. Ponte CG, McManus OB, Schmalhofer WA, et al. Selective, direct activation of high-conductance, calcium-activated potassium channels causes smooth muscle relaxation. Mol Pharmacol American Society for Pharmacology and Experimental Therapeutics. 2012;81:567–77.

    CAS  Google Scholar 

  148. Roy S, MorayoAkande A, Large RJ, et al. Structure-activity relationships of a novel group of large-conductance Ca2+-activated K+ (BK) channel modulators: the GoSlo-SR family. ChemMedChem. 2012;7:1763–9.

    Article  CAS  PubMed  Google Scholar 

  149. Bradley E, Large RJ, Bihun VV, et al. Inhibitory effects of openers of large-conductance Ca2+-activated K+ channels on agonist-induced phasic contractions in rabbit and mouse bronchial smooth muscle. Am J Physiol - Cell Physiol. 2018;315:C818–29.

    Article  CAS  PubMed  Google Scholar 

  150. Zavaritskaya O, Dudem S, Ma D, et al. Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 channels. Br J Pharmacol. 2020;177:1164–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Large RJ, Kshatri A, Webb TI, et al. Effects of the novel BK (KCa1.1) channel opener GoSlo-SR-5–130 are dependent on the presence of BKβ subunits. Br J Pharmacol. 2015;172:2544–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Webb TI, Kshatri AS, Large RJ, et al. Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: involvement of the S4/S5 linker and the S6 segment. Proc Natl Acad Sci U S A. 2015;112:2064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kshatri AS, Li Q, Yan J, et al. Differential efficacy of GoSlo-SR compounds on BKα and BKαγ1–4 channels. Channels. 2017; 66–78

Download references

Funding

This study was supported by the Department of Science and Technology – Brazilian Ministry of Health (DECIT/SCTIE/MS), the Brazilian Council for Scientific and Technological Development (CNPq), the Rio de Janeiro State Research Foundation (FAPERJ), and the Coordination for the Improvement of Higher Education Personnel (CAPES).

Author information

Author notes

  1. Thais S. Barenco-Marins and Fernando A. C. Seara had the same contributions.

Authors and Affiliations

  1. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Thais S. Barenco-Marins, Fernando A. C. Seara & Jose H. M. Nascimento

  2. Programa de Pós-Graduação Em Cardiologia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Thais S. Barenco-Marins & Jose H. M. Nascimento

  3. Instituto de Ciências Biológicas E da Saúde, Universidade Federal Rural Do Rio de Janeiro, Seropédica, RJ, Brazil

    Fernando A. C. Seara

  4. Programa de Pós-Graduação Multicêntrico Em Ciências Fisiológicas, Sociedade Brasileira de Fisiologia, São Paulo, Brazil

    Fernando A. C. Seara

  5. Instituto Federal de Educação, Ciências e Tecnologia do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Cristiano G. Ponte

Authors
  1. Thais S. Barenco-Marins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernando A. C. Seara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristiano G. Ponte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jose H. M. Nascimento
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TSBM and FACS drafted the manuscript and elaborated the figures. CGP, JHMN, and FACS critically revised the manuscript.

Corresponding author

Correspondence to Fernando A. C. Seara.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Barenco-Marins, T.S., Seara, F.A.C., Ponte, C.G. et al. Pulmonary Circulation Under Pressure: Pathophysiological and Therapeutic Implications of BK Channel. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07503-7

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10557-023-07503-7

Keywords

Search

Navigation