arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2017-23-5-360-372arthyper-679Research ArticleРЕДАКЦИОННАЯ СТАТЬЯEDITORIALКОТРАНСПОРТ НАТРИЯ, КАЛИЯ И ХЛОРА КАК РЕГУЛЯТОР СОСУДИСТОГО ТОНУСА: РОЛЬ В ПАТОГЕНЕЗЕ СИСТЕМНОЙ И ЛЕГОЧНОЙ ГИПЕРТЕНЗИИСОTRANSPORTER OF SODIUM, POTASSIUM AND CHLORIDE AS A REGULATOR OF VASCULAR TONE: ROLE IN THE PATHOGENESIS OF SYSTEMIC AND PULMONARY HYPERTENSIONОрловС. Н.OrlovS. N.

Орлов Сергей Николаевич — доктор медицинских наук, профессор, заведующий лабораторией физико-химии биологических мембран ФГБОУ ВО МГУ им. М. В. Ломоносова, главный сотрудник ФГБОУ ВО Сибирский ГМУ Минздрава России.

 

Sergey N. Orlov, MD, PhD, DSc, Professor, Head, Laboratory of Physics and Chemistry of Biological Membranes, Faculty of Biology, MV Lomonosov Moscow State University, Siberian Medical State University.

1/12 Vorob’evy gory, Moscow, 199899. 

sergeinorlov@yandex.ruГусаковаС. В.GusakovaS. V.

Гусакова Светлана Валерьевна — заведующая кафедрой биофизики и функциональной диагностики ФГБОУ ВО Сибирский ГМУ Минздрава России.

Svetlana V. Gusakova, MD, Head, Department of Biophysics and Functional Diagnostics, Siberian Medical State University.

Федеральное государственное бюджетное образовательное  учреждение высшего образования «Московский  государственный университет имени М. В. Ломоносова»; Федеральное государственное бюджетное образовательное учреждение высшего образования  «Сибирский государственный медицинский университет»  Министерства здравоохранения Российской Федерации.РоссияLomonosov Moscow State University; Siberian Medical State University.Russian FederationФедеральное государственное бюджетное  образовательное учреждение высшего образования  «Сибирский государственный медицинский университет»  Министерства здравоохранения Российской Федерации.РоссияSiberian Medical State University.Russian Federation201702112017235360372Copyright © Орлов С.Н., Гусакова С.В., 20172017Орлов С.Н., Гусакова С.В.Orlov S.N., Gusakova S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/679

В обзоре рассматриваются механизмы вовлечения универсальной изоформы переносчика, осуществляющего электронейтральный симпорт натрия, калия и хлора (Na+, K+, 2Cl–-котранспорт — NKCC1) в регуляцию сокращения гладких мышц сосудов большого и малого кругов кровообращения и патогенез эссенциальной и легочной гипертензии. Особое внимание уделено возможности использования NKCC1 как новой мишени для нормализации кровяного давления. В этой связи рассмотрены данные об ингибировании петлевыми диуретиками — селективными ингибиторами NKCC1 — миогенного ответа резистентных сосудов большого круга кровообращения и афферентной артериолы почки, а также о действии ингаляционных форм этих соединений на гладкомышечные клетки воздухопроводящих путей.

This review summarizes the data on the implication of ubiquitous isoform of the carrier providing electroneutral symport of sodium, potassium and chloride (Na+, K+, 2Cl–-cotransport — NKCC1) in the regulation of smooth muscle contraction in the systemic and pulmonary circulation and its involvement in the pathogenesis of systemic (essential) and pulmonary hypertension with the special emphasis on the usage of NKCC1 as a novel antihypertensive target. In this connection we consider the data on the attenuation of the myogenic tone in the resistant vessels of the systemic circulation and afferent arteriole of the kidney as well as the action of inhaled loop diuretic on the contraction of the airway smooth muscle cells.

котранспорт натриякалия и хлорагладкие мышцы сосудовсокращениемиогенный ответгипертензияNKCC1ReferencesAdragna N, Di Fulvio M, Lauf PK. Regulation of K-Cl cotransport: from function to genes. J Membr Biol. 2004;201(3): 109–137. doi:10.1007/s00232–004–0695–6Adragna N, Di Fulvio M, Lauf PK. Regulation of K-Cl cotransport: from function to genes. J Membr Biol. 2004;201(3): 109–137. doi:10.1007/s00232–004–0695–6Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol. 2005;85(2): 423–493. doi:10.1152/physrev.00011.2004Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol. 2005;85(2): 423–493. doi:10.1152/physrev.00011.2004Orlov SN, Mongin AA. Salt sensing mechanisms in blood pressure regulation and hypertension. Am J Physiol Heart Circ Physiol. 2007;293: H2039-H2053. doi:10.1152/ ajpheart.00325.2007Orlov SN, Mongin AA. Salt sensing mechanisms in blood pressure regulation and hypertension. Am J Physiol Heart Circ Physiol. 2007;293: H2039-H2053. doi:10.1152/ ajpheart.00325.2007Markadieu N, Delpire E. Physiology and pathophysiology of SLC12A1/2 transporters. Pfluger Arch Eur J Physiol. 2014;466(1): 91–105. doi:10.1007/s00424–013–1370–5Markadieu N, Delpire E. Physiology and pathophysiology of SLC12A1/2 transporters. Pfluger Arch Eur J Physiol. 2014;466(1): 91–105. doi:10.1007/s00424–013–1370–5Орлов С. Н., Кольцова С. В., Капилевич Л. В., Дулин Н. О., Гусакова С. В. Котранспортеры катионов и хлора: регуляция, физиологическое значение и роль в патогенезе артериальной гипертензии. Успехи биологической химии. 2014;54:267–298. [Orlov SN, Koltsova SV, R Kapilevich LV, Dulin NO, Gusakova SV. Cation and chlorine cotransporters: regulation, physiological significance and role in pathogenesis of arterial hypertension. Uspehi Biologicheskoy Khimii = Biological Chemistry Reviews. 2014;54:267–298. In Russian].Орлов С. Н., Кольцова С. В., Капилевич Л. В., Дулин Н. О., Гусакова С. В. Котранспортеры катионов и хлора: регуляция, физиологическое значение и роль в патогенезе артериальной гипертензии. Успехи биологической химии. 2014;54:267–298. [Orlov SN, Koltsova SV, R Kapilevich LV, Dulin NO, Gusakova SV. Cation and chlorine cotransporters: regulation, physiological significance and role in pathogenesis of arterial hypertension. Uspehi Biologicheskoy Khimii = Biological Chemistry Reviews. 2014;54:267–298. In Russian].Pearson G, Robinson F, Beers GT, Xu BE, Karandikar M, Berman K et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrinology. 2001;22:153–183. doi:10.1210/edrv.22.2.0428Pearson G, Robinson F, Beers GT, Xu BE, Karandikar M, Berman K et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrinology. 2001;22:153–183. doi:10.1210/edrv.22.2.0428Orlov SN, Tremblay J, Hamet P. NKCC1 and hypertension: a novel therapeutic target involved in regulation of vascular tone and renal function. Curr Opin Nephrol Hypert. 2010;19:163–168. doi:10.1097/MNH.0b013e3283360a46Orlov SN, Tremblay J, Hamet P. NKCC1 and hypertension: a novel therapeutic target involved in regulation of vascular tone and renal function. Curr Opin Nephrol Hypert. 2010;19:163–168. doi:10.1097/MNH.0b013e3283360a46Orlov SN, Koltsova SV, Tremblay J, Baskakov MB, Hamet P. NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone. Ann Med. 2012;44: S111-S118. doi:10.3109/07853890.2011.653395Orlov SN, Koltsova SV, Tremblay J, Baskakov MB, Hamet P. NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone. Ann Med. 2012;44: S111-S118. doi:10.3109/07853890.2011.653395Orlov SN. NKCC1 as an epigenetically regulated transporter involved in blood pressure elevation with age. Am J Hypertens. 2011;24:1264. doi:10.1038/ajh.2011.150Orlov SN. NKCC1 as an epigenetically regulated transporter involved in blood pressure elevation with age. Am J Hypertens. 2011;24:1264. doi:10.1038/ajh.2011.150Orlov SN, Koltsova SV, Kapilevich LV, Gusakova SV, Dulin NO. NKCC1 and NKCC2: The pathogenetic role of cationchloride cotransporters in hypertension. Gens Dis. 2015;2:186–196. doi:10.1016/j.gendis.2015.02.007Orlov SN, Koltsova SV, Kapilevich LV, Gusakova SV, Dulin NO. NKCC1 and NKCC2: The pathogenetic role of cationchloride cotransporters in hypertension. Gens Dis. 2015;2:186–196. doi:10.1016/j.gendis.2015.02.007Reho JJ, Zheng X, Fisher SA. Smooth muscle contractile diversity in the control of regional circulations. Am J Physiol Heart Circ Physiol. 2014;306(2): H163-H172. doi:10. 1152/ajpheart.00493.2013Reho JJ, Zheng X, Fisher SA. Smooth muscle contractile diversity in the control of regional circulations. Am J Physiol Heart Circ Physiol. 2014;306(2): H163-H172. doi:10. 1152/ajpheart.00493.2013Chipperfield AR, Harper AA. Chloride in smooth muscle. Prog Biophys Mol Biol. 2001;74(3–5):175–221.Chipperfield AR, Harper AA. Chloride in smooth muscle. Prog Biophys Mol Biol. 2001;74(3–5):175–221.Bulley S, Jaggar JH. Cl- channels in smooth muscle cells. Pfluger Arch Eur J Physiol. 2014;466(5):861–872.Bulley S, Jaggar JH. Cl- channels in smooth muscle cells. Pfluger Arch Eur J Physiol. 2014;466(5):861–872.Matchkov VV, Boedtkier DM, Aalkjaer C. The role of Ca2+ activated Cl- channels in blood pressure control. Curr Opin Pharmacol. 2015;21:127–137. doi:10.1016/j.coph.2015.02.003Matchkov VV, Boedtkier DM, Aalkjaer C. The role of Ca2+ activated Cl- channels in blood pressure control. Curr Opin Pharmacol. 2015;21:127–137. doi:10.1016/j.coph.2015.02.003Leblanc N, Forrest AS, Ayon RJ, Wiwchar M, Angermann JE, Pritchard HAT et al. Molecular and functional significance of Ca2+-activated Cl- channels in pulmonary arterial hyperetnsion. Pulm Circ. 2015;5(2):244–268. doi:10.1086/680189Leblanc N, Forrest AS, Ayon RJ, Wiwchar M, Angermann JE, Pritchard HAT et al. Molecular and functional significance of Ca2+-activated Cl- channels in pulmonary arterial hyperetnsion. Pulm Circ. 2015;5(2):244–268. doi:10.1086/680189Forrest AS, Joyce TC, Huebner ML, Ayon RJ, Wiwchar M, Joyce C et al. Increased TMEM16A-enoded calcium-activated chloride channel activity is associated with pulmonary hypertension. Am J Physiol Cell Physiol. 2012;303(12): C1229-C1243. doi:10.1152/ajpcell.00044.2012Forrest AS, Joyce TC, Huebner ML, Ayon RJ, Wiwchar M, Joyce C et al. Increased TMEM16A-enoded calcium-activated chloride channel activity is associated with pulmonary hypertension. Am J Physiol Cell Physiol. 2012;303(12): C1229-C1243. doi:10.1152/ajpcell.00044.2012Sun H, Xia Y, Paudel O, Yang XR, Sham JS. Chronic hypoxia-induced upregulation of Ca2+-activated Cl- channels in pulmonaty artery myocytes: a mechanism contributing to enhanced vasoreactivity. J Physiol. 2012;590(15):3507–3521. doi:10.1113/jphysiol.2012.232520Sun H, Xia Y, Paudel O, Yang XR, Sham JS. Chronic hypoxia-induced upregulation of Ca2+-activated Cl- channels in pulmonaty artery myocytes: a mechanism contributing to enhanced vasoreactivity. J Physiol. 2012;590(15):3507–3521. doi:10.1113/jphysiol.2012.232520Heinze C, Seniuk A, Sokolov MV, Huebner AK, Klementowicz AE, Szijarto IA et al. Disruption of vascular Ca2+activated chloride currents lowers blood pressure. J Clin Invest. 2014;124(2):675–686. doi:10.1172/JCI70025Heinze C, Seniuk A, Sokolov MV, Huebner AK, Klementowicz AE, Szijarto IA et al. Disruption of vascular Ca2+activated chloride currents lowers blood pressure. J Clin Invest. 2014;124(2):675–686. doi:10.1172/JCI70025Kaplan MR, Plotkin MD, Brown D, Hebert SC, Delpire E. Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and glomerular afferent arteriole. J Clin Invest. 1996;98(3):723–730. doi:10.1172/JCI118844Kaplan MR, Plotkin MD, Brown D, Hebert SC, Delpire E. Expression of the mouse Na-K-2Cl cotransporter, mBSC2, in the terminal inner medullary collecting duct, the glomerular and extraglomerular mesangium, and glomerular afferent arteriole. J Clin Invest. 1996;98(3):723–730. doi:10.1172/JCI118844Hubner CA, Lorke DE, Hermans-Borgmeyer I. Expression of the Na-K-2Cl-cotransporter NKCC1 during mouse development. Mech Dev. 2001;102(1–2):267–269.Hubner CA, Lorke DE, Hermans-Borgmeyer I. Expression of the Na-K-2Cl-cotransporter NKCC1 during mouse development. Mech Dev. 2001;102(1–2):267–269.Rust MB, Faulhaber J, Budack M, Pfeffer C, Maritzen T, Didie M et al. Neurogenic mechanisms contribute to hypertension in mice with disruption of the C–Vl-cotransporter KCC3. Circ Res. 2006;98(4):549–556. doi:10.1161/01.RES.0000204449.83861.22Rust MB, Faulhaber J, Budack M, Pfeffer C, Maritzen T, Didie M et al. Neurogenic mechanisms contribute to hypertension in mice with disruption of the C–Vl-cotransporter KCC3. Circ Res. 2006;98(4):549–556. doi:10.1161/01.RES.0000204449.83861.22Boedtkier E, Aalkjaer C. Intracellular pH in the resistance vasculature: regulation and functional implications. J Vasc Res. 2012;49(6):479–496. doi:10.1159/000341235Boedtkier E, Aalkjaer C. Intracellular pH in the resistance vasculature: regulation and functional implications. J Vasc Res. 2012;49(6):479–496. doi:10.1159/000341235Brosius FC, Pisoni RL, Cao X, Deshmukh G, Yannoukakos D, Stuart-Tilley AK et al. AE anion exchager mRNA and protein expression in vascular smooth muscle cells, aorta and renal microvessels. Am J Physiol. 1997;273(6 Pt 2): F1039-F1047.Brosius FC, Pisoni RL, Cao X, Deshmukh G, Yannoukakos D, Stuart-Tilley AK et al. AE anion exchager mRNA and protein expression in vascular smooth muscle cells, aorta and renal microvessels. Am J Physiol. 1997;273(6 Pt 2): F1039-F1047.Davis JPL, Chipperfield AR, Harper AA. Accumulation of intracellular chloride by (Na-K-Cl) cotransport in rat arterial smooth muscle is enhanced in deoxycorticosterone acetate (DOCA)/salt hypertension. J Mol Cell Cardiol. 1993;25(3): 233–237.Davis JPL, Chipperfield AR, Harper AA. Accumulation of intracellular chloride by (Na-K-Cl) cotransport in rat arterial smooth muscle is enhanced in deoxycorticosterone acetate (DOCA)/salt hypertension. J Mol Cell Cardiol. 1993;25(3): 233–237.Anfinogenova YJ, Baskakov MB, Kovalev IV, Kilin AA, Dulin NO, Orlov SN. Cell-volume-dependent vascular smooth muscle contraction: role of Na+, K+, 2Cl- cotransport, intracellular Cl- and L-type Ca2+ channels. Pflugers Arch. Eur J Physiol. 2004;449:42–55. doi:10.1007/s00424–004–1316-zAnfinogenova YJ, Baskakov MB, Kovalev IV, Kilin AA, Dulin NO, Orlov SN. Cell-volume-dependent vascular smooth muscle contraction: role of Na+, K+, 2Cl- cotransport, intracellular Cl- and L-type Ca2+ channels. Pflugers Arch. Eur J Physiol. 2004;449:42–55. doi:10.1007/s00424–004–1316-zHubner CA, Schroeder BC, Ehmke H. Regulation of vascular tone and arterial blood pressure: role of chloride transport in vascular smooth muscle. Pflugers Arch. Eur J Physiol. 2015;467(3):605–614. doi:10.1007/s00424–014–1684-yHubner CA, Schroeder BC, Ehmke H. Regulation of vascular tone and arterial blood pressure: role of chloride transport in vascular smooth muscle. Pflugers Arch. Eur J Physiol. 2015;467(3):605–614. doi:10.1007/s00424–014–1684-y(5) / 2017 371 23(5) / 2017(5) / 2017 371 23(5) / 2017Barthelmebs M, Stephan D, Fontaine C, Grima M, Imbs JL. Vascular effects of loop diuretics: an in vivo and in vitro study in the rat. Naunyn-Schmiedebergs Arch Pharmacol. 1994;349 (2):209–216.Barthelmebs M, Stephan D, Fontaine C, Grima M, Imbs JL. Vascular effects of loop diuretics: an in vivo and in vitro study in the rat. Naunyn-Schmiedebergs Arch Pharmacol. 1994;349 (2):209–216.Lavallee SL, Iwamoto LM, Claybaugh JR, Dressel MV, Sato AK, Nakamura KT. Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransporet function. Am J Physiol. 1997;273 (1 Pt 1): L211-L216.Lavallee SL, Iwamoto LM, Claybaugh JR, Dressel MV, Sato AK, Nakamura KT. Furosemide-induced airway relaxation in guinea pigs: relation to Na-K-2Cl cotransporet function. Am J Physiol. 1997;273 (1 Pt 1): L211-L216.Tian R, Aalkjaer C, Andreasen F. Mechanisms behind the relaxing effect of furosemide on the isolated rabbit ear artery. Pharmacol Toxicol. 1990;67(5):406–410.Tian R, Aalkjaer C, Andreasen F. Mechanisms behind the relaxing effect of furosemide on the isolated rabbit ear artery. Pharmacol Toxicol. 1990;67(5):406–410.Kovalev IV, Baskakov MB, Anfinogenova YJ, Borodin YL, Kilin AA, Minochenko IL et al. Effect of Na+, K+, 2Cl- cotransport inhibitor bumetanide on electrical and contractile activity of smooth muscle cells in guinea pig ureter. Bull Exp Biol Med. 2003;136(8):145–149.Kovalev IV, Baskakov MB, Anfinogenova YJ, Borodin YL, Kilin AA, Minochenko IL et al. Effect of Na+, K+, 2Cl- cotransport inhibitor bumetanide on electrical and contractile activity of smooth muscle cells in guinea pig ureter. Bull Exp Biol Med. 2003;136(8):145–149.Ковалев И. В., Баскаков М. Б., Медведев М. А., Миноченко И. Л., Килин А. А., Анфиногенова Я. Д. и др.. Изучение роли Na+, K+, 2Cl-котранспорта и хлорной проводимости мембраны в регуляции электрической и сократительной активности гладкомышечных клеток мочеточника морской свинки мезатономигистамином. Российский физиологический журнал им. И. М. Сеченова. 2007;93:306–317. [Kovalev IV, Baskakov MB, Medvedev MA, Minochenko IL, Kilin AA, Anfinogenova YJ, Borodin IV, Gusakova SV, Popov AG, Kapilevich LV, Orlov SN. Na+, K+, 2Cl-cotransport and chloride permeability of the cell membrane in mezaton and histamine regulation of electrical and contractile activity in smooth muscle cells from the guinea pig ureter. Rossiyskiy fiziologicheskiy zhurnal im. IM Sechenova = Ross Fiziol Zh Im I M Sechenova. 2007;93:306–317. In Russian]Ковалев И. В., Баскаков М. Б., Медведев М. А., Миноченко И. Л., Килин А. А., Анфиногенова Я. Д. и др.. Изучение роли Na+, K+, 2Cl-котранспорта и хлорной проводимости мембраны в регуляции электрической и сократительной активности гладкомышечных клеток мочеточника морской свинки мезатономигистамином. Российский физиологический журнал им. И. М. Сеченова. 2007;93:306–317. [Kovalev IV, Baskakov MB, Medvedev MA, Minochenko IL, Kilin AA, Anfinogenova YJ, Borodin IV, Gusakova SV, Popov AG, Kapilevich LV, Orlov SN. Na+, K+, 2Cl-cotransport and chloride permeability of the cell membrane in mezaton and histamine regulation of electrical and contractile activity in smooth muscle cells from the guinea pig ureter. Rossiyskiy fiziologicheskiy zhurnal im. IM Sechenova = Ross Fiziol Zh Im I M Sechenova. 2007;93:306–317. In Russian]Stanke F, Devillier P, Breant D, Chavanon O, Sessa C, Bricca G et al. Furosemide inhibits angiotensin II-induced contraction on human vascular smooth muscle. Br J Clin Pharmacol. 1998;46(6):571–575.Stanke F, Devillier P, Breant D, Chavanon O, Sessa C, Bricca G et al. Furosemide inhibits angiotensin II-induced contraction on human vascular smooth muscle. Br J Clin Pharmacol. 1998;46(6):571–575.Stanke-Labesque F, Craciwski JL, Bedouch P, Chavanon O, Magne JL, Bessard G et al. Furosemide inhibits thrombaxane A2-induced contraction in isolated human internal artery and saphenous vein. J Cardiovasc Pharmacol. 2000;35(4):531–537.Stanke-Labesque F, Craciwski JL, Bedouch P, Chavanon O, Magne JL, Bessard G et al. Furosemide inhibits thrombaxane A2-induced contraction in isolated human internal artery and saphenous vein. J Cardiovasc Pharmacol. 2000;35(4):531–537.Wang X, Breaks J, Loutzenhiser K, Loutzenhiser R. Effects of inhibition of the Na+/K+/2Cl- cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole. Am J Physiol Renal Physiol. 2007;292(3): F999-F1006. doi:10. 1152/ajprenal.00343.2006Wang X, Breaks J, Loutzenhiser K, Loutzenhiser R. Effects of inhibition of the Na+/K+/2Cl- cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole. Am J Physiol Renal Physiol. 2007;292(3): F999-F1006. doi:10. 1152/ajprenal.00343.2006Mozhayeva MG, Bagrov YY. The inhibitory effects of furosemide on Ca2+ influx pathways associated with oxytocininduced contractions of rat myometrium. Gen Physiol Biophys. 1995;14(5):427–436. 36. Mozhayeva MG, Bagrov YY, Ostretsova IB, Gillespie JI. The effect of furosemide on oxytocin-induced contractions of the rat myometrium. Exp Physiol. 1994;79(5):661–667.Mozhayeva MG, Bagrov YY. The inhibitory effects of furosemide on Ca2+ influx pathways associated with oxytocininduced contractions of rat myometrium. Gen Physiol Biophys. 1995;14(5):427–436. 36. Mozhayeva MG, Bagrov YY, Ostretsova IB, Gillespie JI. The effect of furosemide on oxytocin-induced contractions of the rat myometrium. Exp Physiol. 1994;79(5):661–667.Akar F, Skinner E, Klein JD, Jena M, Paul RJ, O'Neill WC. Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl- cotransporter in rat aorta. Am J Physiol. 1999;276 (6 Pt 1): C1383-C1390.Akar F, Skinner E, Klein JD, Jena M, Paul RJ, O'Neill WC. Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl- cotransporter in rat aorta. Am J Physiol. 1999;276 (6 Pt 1): C1383-C1390.Garg P, Martin C, Elms SC, Gordon FJ, Wall SM, Garland CJ et al. Effect of the Na-K-2Cl cotransporter NKCC1 on systematic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol. 2007;29(5): H2100-H2105. doi:10. 1152/ajpheart.01402.2006Garg P, Martin C, Elms SC, Gordon FJ, Wall SM, Garland CJ et al. Effect of the Na-K-2Cl cotransporter NKCC1 on systematic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol. 2007;29(5): H2100-H2105. doi:10. 1152/ajpheart.01402.2006Palacios J, Espinoza F, Munita C, Cifuentes F, Michea L. Na+-K+-2Cl- cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine. Br J Pharmacol. 2006;148(7):964–972. doi:10.1038/sj.bjp.0706818Palacios J, Espinoza F, Munita C, Cifuentes F, Michea L. Na+-K+-2Cl- cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine. Br J Pharmacol. 2006;148(7):964–972. doi:10.1038/sj.bjp.0706818Koltsova SV, Maximov GV, Kotelevtsev SV, Lavoie JL, Tremblay J, Grygorczyk R, Hamet P, Orlov SN. Myogenic tome in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl-cotransport-dependent signaling. Purinergic Signaling. 2009;5:343–349.Koltsova SV, Maximov GV, Kotelevtsev SV, Lavoie JL, Tremblay J, Grygorczyk R, Hamet P, Orlov SN. Myogenic tome in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na+, K+, 2Cl-cotransport-dependent signaling. Purinergic Signaling. 2009;5:343–349.Valero M, Pereboom D, Garay RP, Alda JO. Role of chloride transport proteins in the vasorelaxant action of nitroprusside in isolated rat aorta. Eur J Pharmacol. 2006;553 (1–3):205–208. doi:10.1016/j.ejphar.2006.09.015Valero M, Pereboom D, Garay RP, Alda JO. Role of chloride transport proteins in the vasorelaxant action of nitroprusside in isolated rat aorta. Eur J Pharmacol. 2006;553 (1–3):205–208. doi:10.1016/j.ejphar.2006.09.015Koltsova SV, Kotelevtsev SV, Tremblay J, Hamet P, Orlov SN. Excitation-contraction coupling in resistant mesenteric arteries: evidence for NKCC1-mediated pathway. Biochem.Biophys.Res. Commun. 2009;379:1080–1083.Koltsova SV, Kotelevtsev SV, Tremblay J, Hamet P, Orlov SN. Excitation-contraction coupling in resistant mesenteric arteries: evidence for NKCC1-mediated pathway. Biochem.Biophys.Res. Commun. 2009;379:1080–1083.Dayioglu E, Buharalioglu K, Saracoglu F, Akar F. The effects of bumetanide on human umbilical artery contractions. Reproductive Sci. 2007;14(3):246–252. doi:10.1177/1933719107300871Dayioglu E, Buharalioglu K, Saracoglu F, Akar F. The effects of bumetanide on human umbilical artery contractions. Reproductive Sci. 2007;14(3):246–252. doi:10.1177/1933719107300871Koltsova SV, Luneva OG, Lavoie JL, Tremblay J, Maksimov GV, Hamet P, Orlov SN. HCO3-dependent impact of Na+, K+,2Cl- cotransport in vascular smooth muscle excitationcontraction coupling. Cell.Physiol.Biochem. 2009;23:407–414. doi:10.1159/000218187Koltsova SV, Luneva OG, Lavoie JL, Tremblay J, Maksimov GV, Hamet P, Orlov SN. HCO3-dependent impact of Na+, K+,2Cl- cotransport in vascular smooth muscle excitationcontraction coupling. Cell.Physiol.Biochem. 2009;23:407–414. doi:10.1159/000218187Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev. 1999;79(2):387–423.Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiol Rev. 1999;79(2):387–423.Hill MA, Davis MJ, Meininger GA, Potocnik SJ, Murphy TV. Arteriolar myogenic signaling mechanisms: implications for local vascular functions. Clin Hemorheol Microcirc. 2006;34 (1–2):67–79.Hill MA, Davis MJ, Meininger GA, Potocnik SJ, Murphy TV. Arteriolar myogenic signaling mechanisms: implications for local vascular functions. Clin Hemorheol Microcirc. 2006;34 (1–2):67–79.Schubert R, Mulvany MJ. The myogenic response: established facts and attractive hypothesis. Clin Sci. 1999;96 (4):313–326.Schubert R, Mulvany MJ. The myogenic response: established facts and attractive hypothesis. Clin Sci. 1999;96 (4):313–326.Oriowo MA. Chloride channels and a1-adrenoceptormediated pulmonary artery smooth muscle contraction: effect of pulmonary hypertension. Eur J Pharmacol. 2004;506(2):157–163.Oriowo MA. Chloride channels and a1-adrenoceptormediated pulmonary artery smooth muscle contraction: effect of pulmonary hypertension. Eur J Pharmacol. 2004;506(2):157–163.Greenberg S, McGowan C, Xie J, Summer WR. Selective pulmonary and venous smooth muscle relaxation by furosemide: a comparison with morphine. J Pharmacol Exp Ther. 1994;270(3): 1077–1085.Greenberg S, McGowan C, Xie J, Summer WR. Selective pulmonary and venous smooth muscle relaxation by furosemide: a comparison with morphine. J Pharmacol Exp Ther. 1994;270(3): 1077–1085.Cotton R, Suarez S, Reese J. Unexpected extra-renal effects of loop diuretics in the preterm neonate. Acta Pediatrica. 2012;101(8): 835–845. doi:10.1111/j.1651–2227.2012.02699.xCotton R, Suarez S, Reese J. Unexpected extra-renal effects of loop diuretics in the preterm neonate. Acta Pediatrica. 2012;101(8): 835–845. doi:10.1111/j.1651–2227.2012.02699.xPostnov YuV, Orlov SN. Ion transport across plasma membrane in primary hypertension. Physiol Rev. 1985;65:904–945Postnov YuV, Orlov SN. Ion transport across plasma membrane in primary hypertension. Physiol Rev. 1985;65:904–945Orlov SN, Adragna N, Adarichev VA, Hamet P. Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. Am J Physiol. 1999;276: C511-C536Orlov SN, Adragna N, Adarichev VA, Hamet P. Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. Am J Physiol. 1999;276: C511-C536Garay RP, Alda O. What can we learn from erythrocyte NaK-Cl cotransporter NKCC1 in human hypertension? Pathophysiology. 2007;14(3–4):167–170. doi:10.1016/j.pathophys.2007.09.006Garay RP, Alda O. What can we learn from erythrocyte NaK-Cl cotransporter NKCC1 in human hypertension? Pathophysiology. 2007;14(3–4):167–170. doi:10.1016/j.pathophys.2007.09.006Korpi ER, Luddens H. Furosemide interactions with brain GABAA receptors. Br J Pharmacol. 1997;120(5):741–748.Korpi ER, Luddens H. Furosemide interactions with brain GABAA receptors. Br J Pharmacol. 1997;120(5):741–748.Lee HA, Baek I, Seok YM, Yang E, Cho HM, Lee DY et al. Promoter hypomethylation upregulates Na+-K+-2Cl- cotransporter 1 in spontaneously hypertensive rats. Biochem Biophys Res Commun. 2010;396(2):252–257. doi:10.1016/j.bbrc.2010.04.074Lee HA, Baek I, Seok YM, Yang E, Cho HM, Lee DY et al. Promoter hypomethylation upregulates Na+-K+-2Cl- cotransporter 1 in spontaneously hypertensive rats. Biochem Biophys Res Commun. 2010;396(2):252–257. doi:10.1016/j.bbrc.2010.04.074Ye ZY, Li DP, Byun HS, Li L, Pan HL. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal-sympathetic drive in hypertension. J Neurosci. 2012;32(25): 8560–8568. doi:10.1523/JNEUROSCI.1346–12.2012Ye ZY, Li DP, Byun HS, Li L, Pan HL. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal-sympathetic drive in hypertension. J Neurosci. 2012;32(25): 8560–8568. doi:10.1523/JNEUROSCI.1346–12.2012Cho HM, Lee HA, Kim HY, Han HS, Kim IK. Expression of Na+, K+-2Cl- cotransporter is epigenetically regulated during postnatal development of hypertension. Am J Hypertens. 2011;24(12): 1286–1293. doi:10.1038/ajh.2011.136Cho HM, Lee HA, Kim HY, Han HS, Kim IK. Expression of Na+, K+-2Cl- cotransporter is epigenetically regulated during postnatal development of hypertension. Am J Hypertens. 2011;24(12): 1286–1293. doi:10.1038/ajh.2011.136Brown RA, Chipperfield AR, Davis JPL, Harper AA. Increased (Na+K+Cl-) cotransport in rat arterial smooth muscle in deoxycorticosterone (DOCA)/salt-induced hypertension. J Vasc Res. 1999;36(6):492–501.Brown RA, Chipperfield AR, Davis JPL, Harper AA. Increased (Na+K+Cl-) cotransport in rat arterial smooth muscle in deoxycorticosterone (DOCA)/salt-induced hypertension. J Vasc Res. 1999;36(6):492–501.Jiang G, Akar F, Cobbs SL, Lomashvilli K, Lakkis R, Gordon FJ et al. Blood pressure regulates the activity and function of Na-K-2Cl cotransporter in vascular smooth muscle. Am J Physiol Heart Circ Physiol. 2004;286(4): H1552-H1557. doi:10.1152/ajpheart.00695.2003Jiang G, Akar F, Cobbs SL, Lomashvilli K, Lakkis R, Gordon FJ et al. Blood pressure regulates the activity and function of Na-K-2Cl cotransporter in vascular smooth muscle. Am J Physiol Heart Circ Physiol. 2004;286(4): H1552-H1557. doi:10.1152/ajpheart.00695.2003Jiang G, Cobbs S, Klein JD, O'Neill WC. Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle. Hypertension. 2003;41(5):1131–1135. doi:10.1161/01.HYP. 0000066128.04083.CAJiang G, Cobbs S, Klein JD, O'Neill WC. Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle. Hypertension. 2003;41(5):1131–1135. doi:10.1161/01.HYP. 0000066128.04083.CADing B, Frisina RD, Zhu X, Sakai Y, Sokolowski B, Walton JP. Direct control of Na+-K+-2Cl- cotransport protein (NKCC1) expression with aldosterone. Am J Physiol Cell Physiol. 2014;306(1): C66-C75. doi:10.1152/ajpcell.00096.2013Ding B, Frisina RD, Zhu X, Sakai Y, Sokolowski B, Walton JP. Direct control of Na+-K+-2Cl- cotransport protein (NKCC1) expression with aldosterone. Am J Physiol Cell Physiol. 2014;306(1): C66-C75. doi:10.1152/ajpcell.00096.2013Cho HM, Lee DY, Kim HY, Lee HA, Seok YM, Kim IK. Upregulation of the Na+-K+-2Cl- cotransporter 1 via histone modification in the aortas of angiotensin IIinduced hypertensive rats. Hypertens.Res. 2012;35(8):819–824. doi:10.1038/hr.2012.37Cho HM, Lee DY, Kim HY, Lee HA, Seok YM, Kim IK. Upregulation of the Na+-K+-2Cl- cotransporter 1 via histone modification in the aortas of angiotensin IIinduced hypertensive rats. Hypertens.Res. 2012;35(8):819–824. doi:10.1038/hr.2012.37Orlov SN. Decreased Na+, K+, Cl-cotransport and salt retention in Blacks: a provocative hypothesis. J. Hypertens. 2005;23:1929–1930.Orlov SN. Decreased Na+, K+, Cl-cotransport and salt retention in Blacks: a provocative hypothesis. J. Hypertens. 2005;23:1929–1930.Boone CA. End-stage renal disease in African-Americans. Nephrol Nurs J. 2000;27(6):597–600.Boone CA. End-stage renal disease in African-Americans. Nephrol Nurs J. 2000;27(6):597–600.Orlov SN, Gossard F, Pausova Z, Akimova OA, Tremblay J, Grim CE et al. Decreased NKCC1 activity in erythrocytes from African-Americans with hypertension and dyslipidemia. Am J Hypertens. 2010;23:321–326. doi:10.1038/ajh.2009.249Orlov SN, Gossard F, Pausova Z, Akimova OA, Tremblay J, Grim CE et al. Decreased NKCC1 activity in erythrocytes from African-Americans with hypertension and dyslipidemia. Am J Hypertens. 2010;23:321–326. doi:10.1038/ajh.2009.249Huber LC, Bye H, Brock M. The pathogenesis of pulmonary hypertension — an update. Swiss Medical Weekly. 2015;145: w14202. doi:10.4414/smw.2015.14202Huber LC, Bye H, Brock M. The pathogenesis of pulmonary hypertension — an update. Swiss Medical Weekly. 2015;145: w14202. doi:10.4414/smw.2015.14202Kanwar MK, Thenappan T, Vachiery JL. Update in treatment options in pulmonary hypertension. J Heart Lung Transplant. 2016;35(6):695–703. doi:10.1016/j.healun.2016.01.020Kanwar MK, Thenappan T, Vachiery JL. Update in treatment options in pulmonary hypertension. J Heart Lung Transplant. 2016;35(6):695–703. doi:10.1016/j.healun.2016.01.020Noordegraaf AV, Groeneveldt JA, Bogaard HJ. Pulmonary hypertension. Eur Respir Rev. 2016;25(139):4–11. doi:10.1183/16000617.0096–2015Noordegraaf AV, Groeneveldt JA, Bogaard HJ. Pulmonary hypertension. Eur Respir Rev. 2016;25(139):4–11. doi:10.1183/16000617.0096–2015Cuttica MJ. Pulmonary hypertension associated with lung diseases and hypoxemia. Heart Fail Rev. 2016;21(3):299–308. doi:10.1007/s10741–016–9551-xCuttica MJ. Pulmonary hypertension associated with lung diseases and hypoxemia. Heart Fail Rev. 2016;21(3):299–308. doi:10.1007/s10741–016–9551-xHambly N, Alawfi F, Mehta S. Pulmonary hypertension: diagnostic approach and optimal management. CMAJ. 2016;188 (11):804–12. doi:10.1503/cmaj.151075Hambly N, Alawfi F, Mehta S. Pulmonary hypertension: diagnostic approach and optimal management. CMAJ. 2016;188 (11):804–12. doi:10.1503/cmaj.151075Velayti A, Valerio MG, Shen D, Tariq S, Lanier GM, Aronow WS. Update on pulmonary arterial hypertension pharmacotherapy. Postgraduate Medicine. 2016;128(5):460–473. doi:10.1080/00325481.2016.1188664Velayti A, Valerio MG, Shen D, Tariq S, Lanier GM, Aronow WS. Update on pulmonary arterial hypertension pharmacotherapy. Postgraduate Medicine. 2016;128(5):460–473. doi:10.1080/00325481.2016.1188664Hu J, Xu Q, McTiernan C, Lai YC, Osei-Hwedieh D, Gladwin M. Novel targets of drug treatment for pulmonary hypertension. Am J Cardiovasc Drugs. 2015;15(4):225–234. doi:10.1007/s40256–015–0125–4Hu J, Xu Q, McTiernan C, Lai YC, Osei-Hwedieh D, Gladwin M. Novel targets of drug treatment for pulmonary hypertension. Am J Cardiovasc Drugs. 2015;15(4):225–234. doi:10.1007/s40256–015–0125–4Humbert M, Ghofrani HS. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71(1):73–83. doi:10.1136/thoraxjnl-2015–207170Humbert M, Ghofrani HS. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71(1):73–83. doi:10.1136/thoraxjnl-2015–207170Bianco S, Robuschi M, Vaghi A, Fumagall A, Sestini P. Inhaled transmembrane ion transport modulators and non-steroidal anti-inflammatory drugs in asthma. Thorax. 2000;55 (suppl 2): S48-S50.Bianco S, Robuschi M, Vaghi A, Fumagall A, Sestini P. Inhaled transmembrane ion transport modulators and non-steroidal anti-inflammatory drugs in asthma. Thorax. 2000;55 (suppl 2): S48-S50.Inokuchi R, Aoki A, Aoki Y, Yahagi N. Effectiveness of inhaled furosemide for acute asthma exacerbation: a meta-analysis. Crit Care. 2014;18(6):621. doi:10.1186/s13054–014–0621-yInokuchi R, Aoki A, Aoki Y, Yahagi N. Effectiveness of inhaled furosemide for acute asthma exacerbation: a meta-analysis. Crit Care. 2014;18(6):621. doi:10.1186/s13054–014–0621-ySpicuzza L, Ciancio N, Pellegrino R, Bellofiore S, Polosa R, Ricciardolo FL et al. The effect of inhaled furosemide and acetazolamide on broncoconstriction induced by deep inspiration in asthma. Monaldi Arch Chest Dis. 2003;59(2):150–154.Spicuzza L, Ciancio N, Pellegrino R, Bellofiore S, Polosa R, Ricciardolo FL et al. The effect of inhaled furosemide and acetazolamide on broncoconstriction induced by deep inspiration in asthma. Monaldi Arch Chest Dis. 2003;59(2):150–154.Cavaliere F, Masieri S. Furosemide protective effect against airway obstruction. Curr Drug Targets. 2002;3(3):197–201.Cavaliere F, Masieri S. Furosemide protective effect against airway obstruction. Curr Drug Targets. 2002;3(3):197–201.Masoumi K, Forouzan A, Shoushtari MH, Porozan S, Feli M, Sheidaee MFB et al. The efficacy of neubulized furosemide and salbutamol compared with salbutamol alone in reactive airway: a double blind randomized, clinical trial. Emerg Med Int. 2014;2014:638102. doi:10.1155/2014/638102Masoumi K, Forouzan A, Shoushtari MH, Porozan S, Feli M, Sheidaee MFB et al. The efficacy of neubulized furosemide and salbutamol compared with salbutamol alone in reactive airway: a double blind randomized, clinical trial. Emerg Med Int. 2014;2014:638102. doi:10.1155/2014/638102Bialasiewicz P, Wlodarczyk A, Dudkiewicz B, Nowak D. Inhibitory effect of furosemide on activation of human peripheral blood plymorphonuclear leukocytes stimulated with n-gormyl-methionyl-leucyl-phenylalanine. Int.Immunopharmacol. 2004;4(6):819–831. doi:10.1016/j.intimp.2004.01.024Bialasiewicz P, Wlodarczyk A, Dudkiewicz B, Nowak D. Inhibitory effect of furosemide on activation of human peripheral blood plymorphonuclear leukocytes stimulated with n-gormyl-methionyl-leucyl-phenylalanine. Int.Immunopharmacol. 2004;4(6):819–831. doi:10.1016/j.intimp.2004.01.024Iwamoto LM, Fujiwara N, Nakamura KT, Wada RK. Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation. Am. J. Physiol.Lung Cell Mol Physiol. 2004;287(3): L510-L514. doi: 10.1152/ajplung.00021.2004Iwamoto LM, Fujiwara N, Nakamura KT, Wada RK. Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation. Am. J. Physiol.Lung Cell Mol Physiol. 2004;287(3): L510-L514. doi: 10.1152/ajplung.00021.2004Salvi SS. a1-Adrenergic hypothesis for pulmonary hypertension. Chest. 1999;115(6):1708–1719.Salvi SS. a1-Adrenergic hypothesis for pulmonary hypertension. Chest. 1999;115(6):1708–1719.Molimard M, Naline E, Hirsch A, Advenier C. Furosemide inhibits bradykinin-induced contraction of human brochi: role of thromboxane A2 receptor antagonism. Eur J Pharmacol. 1995;278(3):253–256.Molimard M, Naline E, Hirsch A, Advenier C. Furosemide inhibits bradykinin-induced contraction of human brochi: role of thromboxane A2 receptor antagonism. Eur J Pharmacol. 1995;278(3):253–256.Meyer JW, Flagella M, Sutliff RL, Lorenz JN, Nieman ML, Weber GS, et al. Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na+-K+2Cl- cotransporter. Am J Physiol. 2002;283(5): H1846-H1855. doi:10.1152/ajpheart.00083.2002Meyer JW, Flagella M, Sutliff RL, Lorenz JN, Nieman ML, Weber GS, et al. Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na+-K+2Cl- cotransporter. Am J Physiol. 2002;283(5): H1846-H1855. doi:10.1152/ajpheart.00083.2002Fortuno A, Muniz P, Ravassa S, Rodriguez JA, Fortuno A, Zalba G et al. Torasemide inhibits angiotensin IIinduced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999;34(1): 138–143.Fortuno A, Muniz P, Ravassa S, Rodriguez JA, Fortuno A, Zalba G et al. Torasemide inhibits angiotensin IIinduced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999;34(1): 138–143.Shen B, Fu J, Guo J, Zhang J, Wang X, Pan X et al. Role of Na+-K+-2Cl- cotransporter 1 in phenylephrine-induced rhytmic contraction in the mouse aorta: regulation of Na+-K+-2Cl- cotransporter 1 by Ca2+ sparks and KCa channels. Cell Physiol Biochem. 2015;37(2):747–758. doi: 10.1159/000430392Shen B, Fu J, Guo J, Zhang J, Wang X, Pan X et al. Role of Na+-K+-2Cl- cotransporter 1 in phenylephrine-induced rhytmic contraction in the mouse aorta: regulation of Na+-K+-2Cl- cotransporter 1 by Ca2+ sparks and KCa channels. Cell Physiol Biochem. 2015;37(2):747–758. doi: 10.1159/000430392

The authors declare that there are no conflicts of interest present.