vestnik-bio-msuВестник Московского университета. Серия 16. БиологияVestnik Moskovskogo universiteta. Seriya 16. Biologiya0137-0952Lomonosov Moscow State University, School of Biology10.55959/MSU0137-0952-16-78-4-7vestnik-bio-msu-1227Research ArticleОРИГИНАЛЬНОЕ ИССЛЕДОВАНИЕRESEARCH ARTICLEВлияние пробенецида на проаритмические эффекты активации альфа-1-адренорецепторов в атриовентрикулярном узле сердца крысыThe effect of probenecid on α-1-adrenoceptor stimulation induced proarrhythmic conduction in the atrioventricular node of rat hearthttps://orcid.org/0000-0001-6624-7805ВоронинаЯ. А.VoroninaY. A.

Воронина Яна Алексеевна – ассистент кафедры физиологии человека и животных биологического факультета МГУ

Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University

voronina.yana.2014@post.bio.msu.ruhttps://orcid.org/0000-0003-3075-4834КузьминВ. С.KuzminV. S.

Кузьмин Владислав Стефанович – докт. биол. наук, доц. кафедры физиологии человека и животных биологического факультета МГУ

Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University

ku290381@mail.ruМосковский государственный университет имени М.В. ЛомоносоваРоссияLomonosov Moscow State UniversityRussian Federation202327022024784258266Copyright © Воронина Я.А., Кузьмин В.С., 20232023Воронина Я.А., Кузьмин В.С.Voronina Y.A., Kuzmin V.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestnik-bio-msu.elpub.ru/jour/article/view/1227

В ткани сердца присутствуют адренорецепторы (АР) не только бета-типа, но и альфа-типа (α-АР). Оба типа АР принимают участие в регуляции электрической активности кардиомиоцитов различных отделов сердца, включая кардиомиоциты атриовентрикулярного узла (АВУ). Смещение баланса передачи адренергических сигналов в сторону α1-АР способствует появлению нарушений проведения возбуждения в различных отделах сердца и возникновению аритмий. Поскольку активация α1-АР усиливает анионную проводимость, цель настоящей работы заключалась в изучении влияния блокады хлорных каналов на α-адренергические нарушения АВУ-проведения возбуждения. Для этого оценивали время проведения в АВУ, рефрактерность АВУ и характер нарушений проведения в АВУ с помощью методики изолированного по Лангендорфу сердца крысы (самцы Wistar, 250 ± 30 г) с регистрацией предсердной и желудочковой электрограмм. В качестве агониста α1-АР использовали фенилэфрин (ФЭ, 10 µМ), в качестве блокатора анионной (хлорной) проводимости использовали пробенецид (100 µМ). Установили, что активация α1-АР их агонистом ФЭ приводит к статистически значимому увеличению длительности атриовентрикулярной задержки (N = 10, p < 0,001) и эффективного рефрактерного периода (ЭРП) на 9,8% ± 1,2%, (N = 10, p < 0,001) в АВУ. При частоте стимуляции, близкой к ЭРП, ФЭ индуцирует блоки проведения в АВУ и осцилляции длительности задержки в АВУ (N = 10). При нестационарном характере проведения возбуждения в АВУ на фоне ФЭ пробенецид статистически значимо уменьшает величину осцилляций длительности задержки в АВУ. Кроме того, ЭРП при действии ФЭ на фоне пробенецида оказывается более коротким (107 ± 4 мс – ФЭ на фоне пробенецида, 114,2 ± 5,35 мс – ФЭ), то есть возвращается к значениям, характерным для нормальных условий. В итоге пробенецид способствует поддержанию проведения в АВУ на фоне активации α1-АР. Подавление пробенецидом проаритмических эффектов активации α1-АР в АВУ указывает на вовлеченность хлорных ионных каналов и анионных переносчиков в формирование аритмий в АВУ.­

Cardiac tissue contains adrenergic receptors (AR) not only of the beta type, but also of the alpha type (α-AR). Both types of ARs play significant role in regulation of cardiomyocytes electrophysiology in different parts of the heart, including the atrioventricular node (AVN). An augmentation of α1-AR mediated component of adrenergic signaling results in impaired conduction of excitation in the heart and onset of various rhythm disturbances including AVN-associated arrhythmias. The activation of α1-AR facilitates anionic transmembrane transport causing electrophysiological changes in myocytes. Current study is aimed to the investigation of the effects of anion/chloride blockade on α1-AR-mediated proarrhythmic alteration of AVN functioning. Functional characteristics of AVN including AVN conduction time, AVN refractoriness and the AVN conduction alterations were examined via recording of surface electrograms in Langendorff-perfused isolated rat heart (Wistar, 250 ± 30 g). Phenylephrine was used as α1-AR agonist. Probenecid demonstrating anion/chloride transmembrane conductance blocking activity was used to modify Phe-induced α1-AR-mediated effects in AVN. The activation of α1-AR by Phe results in a significant increase in the duration of AV intervals (N = 10, p < 0.001) and effective refractory period (ERP) in the AVN (by 9.8% ± 1.2%, n = 10, p < 0.001). Also, Phe induces AV-blocks of conduction and oscillations in atrioventricular delay (N = 10) at the stimulation rates close to ERP. Probenecid significantly reduces the magnitude of AVD oscillations during non-stationary conduction in the AV node. In addition, probenecid attenuates ERP prolongation caused by Phe (107 ± 4 ms, N = 6) and 114.2 ± 5.35 ms (N = 10) in presence of only Phe and Phe with probenecid, respectively, returning its values toward typical for normal conditions. In conclusion, probenecid maintains physiological mode of AVN conduction when α1-AR are stimulated. This also suggests that chloride ion channels and anion carriers may contribute to the α1-AR-mediated AVN arrhythmias.

α1-адренорецепторыатриовентрикулярный узелатриовентрикулярные блокипробенецидхлорные каналыаритмияα1-adrenergic receptorsatrioventricular nodeatrioventricular blocksprobenecidchloride channelsarrhythmiaРабота выполнена при поддержке Российского научного фонда (проект №22-15-00189)The research was funded by Russian Science Foundation, project number 22-15-00189ReferencesBignolais O., Quang K. Le, Naud P., El Harchi A., Briec F., Piron J., Bourge A., Leoni A.L., Charpentier F., Demolombe S. Early ion-channel remodeling and arrhythmias precede hypertrophy in a mouse model of complete atrioventricular block. J. Mol. Cell. Cardiol. 2011;51(5):713–721.Bignolais O., Quang K. Le, Naud P., El Harchi A., Briec F., Piron J., Bourge A., Leoni A.L., Charpentier F., Demolombe S. Early ion-channel remodeling and arrhythmias precede hypertrophy in a mouse model of complete atrioventricular block. J. Mol. Cell. Cardiol. 2011;51(5):713–721.Zhao X., Sun C., Cao M., Li H. Atrioventricular block can be used as a risk predictor of clinical atrial fibrillation. Clin. Cardiol. 2019; 42(4): 452–458.Zhao X., Sun C., Cao M., Li H. Atrioventricular block can be used as a risk predictor of clinical atrial fibrillation. Clin. Cardiol. 2019; 42(4): 452–458.Lee S., Wellens H.J.J., Josephson M.E. Paroxysmal atrioventricular block. Hear. Rhythm. 2009;6(8):1229–1234.Lee S., Wellens H.J.J., Josephson M.E. Paroxysmal atrioventricular block. Hear. Rhythm. 2009;6(8):1229–1234.Kashou A.H., Kashou H.E. Rhythm, Atrioventricular Block. StatPearls Publishing; 2018. 324 pp.Kashou A.H., Kashou H.E. Rhythm, Atrioventricular Block. StatPearls Publishing; 2018. 324 pp.O’Connell T.D., Jensen B.C., Baker A.J., Simpson P.C. Cardiac alpha1-adrenergic receptors: Novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol. Rev. 2014;66(1):308–333.O’Connell T.D., Jensen B.C., Baker A.J., Simpson P.C. Cardiac alpha1-adrenergic receptors: Novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol. Rev. 2014;66(1):308–333.Takata K., Adachi Y.U., Suzuki K., Obata Y., Sato S., Nishiwaki K. Dexmedetomidine-induced atrioventricular block followed by cardiac arrest during atrial pacing: A case report and review of the literature. J. Anesth. 2014;28(1):116–120.Takata K., Adachi Y.U., Suzuki K., Obata Y., Sato S., Nishiwaki K. Dexmedetomidine-induced atrioventricular block followed by cardiac arrest during atrial pacing: A case report and review of the literature. J. Anesth. 2014;28(1):116–120.Spiers J.P., Harron D.W.G., Wilson R., Allen J.D. UK-52,046 (a novel α1-adrenoceptor antagonist) and the role of α-adrenoceptor stimulation and blockade on atrioventricular conduction. J. Cardiovasc. Pharmacol. 1990;16(5):824–830.Spiers J.P., Harron D.W.G., Wilson R., Allen J.D. UK-52,046 (a novel α1-adrenoceptor antagonist) and the role of α-adrenoceptor stimulation and blockade on atrioventricular conduction. J. Cardiovasc. Pharmacol. 1990;16(5):824–830.Cotecchia S., del Vescovo C.D., Colella M., Caso S., Diviani D. The alpha1-adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications. Cellular Signalling. 2015;27(10):1984–1993.Cotecchia S., del Vescovo C.D., Colella M., Caso S., Diviani D. The alpha1-adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications. Cellular Signalling. 2015;27(10):1984–1993.Одношивкина Ю.Г., Петров А.М. Роль нейро-кардиального соединения в симпатической регуляции сердца. Рос. физиол. журн. им. И.М. Сеченова. 2021;107(4–5):474–491.Одношивкина Ю.Г., Петров А.М. Роль нейро-кардиального соединения в симпатической регуляции сердца. Рос. физиол. журн. им. И.М. Сеченова. 2021;107(4–5):474–491.Gould D.J., Hill C.E. α-Adrenoceptor activation of a chloride conductance in rat iris arterioles. Am. J. Physiol. - Hear. Circ. Physiol. 1996;271(40):2469–2476.Gould D.J., Hill C.E. α-Adrenoceptor activation of a chloride conductance in rat iris arterioles. Am. J. Physiol. - Hear. Circ. Physiol. 1996;271(40):2469–2476.Lamb F.S., Kooy N.W., Lewis S.J. Role of Cl- channels in α-adrenoceptor-mediated vasoconstriction in the anesthetized rat. Eur. J. Pharmacol. 2000;401(3):403–412.Lamb F.S., Kooy N.W., Lewis S.J. Role of Cl- channels in α-adrenoceptor-mediated vasoconstriction in the anesthetized rat. Eur. J. Pharmacol. 2000;401(3):403–412.Robert R., Thoreau V., Norez C., Cantereau A., Kitzis A., Mettey Y., Rogier C., Becq F. Regulation of the cystic fibrosis transmembrane conductance regulator channel by β-adrenergic agonists and vasoactive intestinal peptide in rat smooth muscle cells and its role in vasorelaxation. J. Biol. Chem. 2004;279(20):21160–21168.Robert R., Thoreau V., Norez C., Cantereau A., Kitzis A., Mettey Y., Rogier C., Becq F. Regulation of the cystic fibrosis transmembrane conductance regulator channel by β-adrenergic agonists and vasoactive intestinal peptide in rat smooth muscle cells and its role in vasorelaxation. J. Biol. Chem. 2004;279(20):21160–21168.Robert R., Norez C., Becq F. Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl- transport of mouse aortic smooth muscle cells. J. Physiol. 2005;568(2):483–495.Robert R., Norez C., Becq F. Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl- transport of mouse aortic smooth muscle cells. J. Physiol. 2005;568(2):483–495.Adkins G.B., Curtis M.J. Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol. Ther. 2015;145:67–75.Adkins G.B., Curtis M.J. Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol. Ther. 2015;145:67–75.Duan D.D. Phenomics of cardiac chloride channels. Compr. Physiol. 2013; 3(2): 667–692.Duan D.D. Phenomics of cardiac chloride channels. Compr. Physiol. 2013; 3(2): 667–692.Hume J.R., Duan D., Collier M.L., Yamazaki J., Horowitz B. Anion transport in heart. Physiol. Rev. 2000;80(1):31–81.Hume J.R., Duan D., Collier M.L., Yamazaki J., Horowitz B. Anion transport in heart. Physiol. Rev. 2000;80(1):31–81.Pustovit K.B., Samoilova D.V., Abramochkin D.V., Filatova T.S., Kuzmin V.S. α1-adrenergic receptors accompanied by GATA4 expression are related to proarrhythmic conduction and automaticity in rat interatrial septum. J. Physiol. Biochem. 2022;78(4):793–805.Pustovit K.B., Samoilova D.V., Abramochkin D.V., Filatova T.S., Kuzmin V.S. α1-adrenergic receptors accompanied by GATA4 expression are related to proarrhythmic conduction and automaticity in rat interatrial septum. J. Physiol. Biochem. 2022;78(4):793–805.Egorov Y.V., Kuzmin V.S., Glukhov A.V., Rosenshtraukh L.V. Electrophysiological characteristics, rhythm, disturbances and conduction discontinuities under autonomic stimulation in the rat pulmonary vein myocardium. J. Cardiovasc. Electrophysiol. 2015;26(10):1130–1139.Egorov Y.V., Kuzmin V.S., Glukhov A.V., Rosenshtraukh L.V. Electrophysiological characteristics, rhythm, disturbances and conduction discontinuities under autonomic stimulation in the rat pulmonary vein myocardium. J. Cardiovasc. Electrophysiol. 2015;26(10):1130–1139.Ivanova A.D., Filatova T.S., Abramochkin D. V., Atkinson A., Dobrzynski H., Kokaeva Z.G., Merzlyak E.M., Pustovit K.B., Kuzmin V.S. Attenuation of inward rectifier potassium current contributes to the α1-adrenergic receptor-induced proarrhythmicity in the caval vein myocardium. Acta Physiol. 2021;231(4): e13597.Ivanova A.D., Filatova T.S., Abramochkin D. V., Atkinson A., Dobrzynski H., Kokaeva Z.G., Merzlyak E.M., Pustovit K.B., Kuzmin V.S. Attenuation of inward rectifier potassium current contributes to the α1-adrenergic receptor-induced proarrhythmicity in the caval vein myocardium. Acta Physiol. 2021;231(4): e13597.Kuzmin V.S., Kamensky A.A. The molecular and cellular mechanisms of heart pacemaker development in vertebrates. Moscow Univ. Biol. Sci. Bull. 2021;76(4):147–164.Kuzmin V.S., Kamensky A.A. The molecular and cellular mechanisms of heart pacemaker development in vertebrates. Moscow Univ. Biol. Sci. Bull. 2021;76(4):147–164.Saeed Y., Temple I.P., Borbas Z., Atkinson A., Yanni J., Maczewski M., Mackiewicz U., Aly M., Logantha S.J.R.J., Garratt C.J., Dobrzynski H. Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide–gated and ryanodine 2 channels. Hear. Rhythm. 2018;15(5):752–760.Saeed Y., Temple I.P., Borbas Z., Atkinson A., Yanni J., Maczewski M., Mackiewicz U., Aly M., Logantha S.J.R.J., Garratt C.J., Dobrzynski H. Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide–gated and ryanodine 2 channels. Hear. Rhythm. 2018;15(5):752–760.Markowitz S.M., Lerman B.B. A contemporary view of atrioventricular nodal physiology. J. Interv. Card. Electrophysiol. 2018;52(3):271–279.Markowitz S.M., Lerman B.B. A contemporary view of atrioventricular nodal physiology. J. Interv. Card. Electrophysiol. 2018;52(3):271–279.Yajima T., Tsutsumi-sakai R., Hagiwara N. Vessels functional activity of the CFTR C1- channel in human myocardium. Hear. Vessel. 1997;12(6):255–261.Yajima T., Tsutsumi-sakai R., Hagiwara N. Vessels functional activity of the CFTR C1- channel in human myocardium. Hear. Vessel. 1997;12(6):255–261.Wang Y., Zhao J., Cai Y., Ballard H.J. Cystic fibrosis transmembrane conductance regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation. Acta Physiol. 2020;230(1):e13495.Wang Y., Zhao J., Cai Y., Ballard H.J. Cystic fibrosis transmembrane conductance regulator-dependent bicarbonate entry controls rat cardiomyocyte ATP release via pannexin1 through mitochondrial signalling and caspase activation. Acta Physiol. 2020;230(1):e13495.Sellers Z.M., De Arcangelis V., Xiang Y., Best P.M. Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+-activated Cl- channel activity to maintain contraction rate. J. Physiol. 2010;588(13):2417–2429.Sellers Z.M., De Arcangelis V., Xiang Y., Best P.M. Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+-activated Cl- channel activity to maintain contraction rate. J. Physiol. 2010;588(13):2417–2429.James A.F. Enigmatic variations: The many facets of CFTR function in the heart. Acta Physiol. 2020;230(1):e13525.James A.F. Enigmatic variations: The many facets of CFTR function in the heart. Acta Physiol. 2020;230(1):e13525.Uramoto H., Okada T., Okada Y. Protective role of cardiac CFTR activation upon early reperfusion against myocardial infarction. Cell. Physiol. Biochem. 2012;30(4):1023–1038.Uramoto H., Okada T., Okada Y. Protective role of cardiac CFTR activation upon early reperfusion against myocardial infarction. Cell. Physiol. Biochem. 2012;30(4):1023–1038.Bahinski A., Nairn A.C., Greengard P., Gadsby D.C. Chloride conductance regulated by cyclic AMP-dependent protein kinase in cardiac myocytes. Nature. 1989;340(6236):718–721.Bahinski A., Nairn A.C., Greengard P., Gadsby D.C. Chloride conductance regulated by cyclic AMP-dependent protein kinase in cardiac myocytes. Nature. 1989;340(6236):718–721.Mutlu G.M., Adir Y., Jameel M., Akhmedov A.T., Welch L., Dumasius V., Fan J.M., Zabner J., Koenig C., Lewis E.R., Balagani R., Traver G., Sznajder J.I., Factor P. Interdependency of β-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ. Res. 2005;96(9):999–1005.Mutlu G.M., Adir Y., Jameel M., Akhmedov A.T., Welch L., Dumasius V., Fan J.M., Zabner J., Koenig C., Lewis E.R., Balagani R., Traver G., Sznajder J.I., Factor P. Interdependency of β-adrenergic receptors and CFTR in regulation of alveolar active Na+ transport. Circ. Res. 2005;96(9):999–1005.Vijftigschild L.A.W., Berkers G., Dekkers J.F., et al. 2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. Eur. Respir. J. 2016;48(3):768–779.Vijftigschild L.A.W., Berkers G., Dekkers J.F., et al. 2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. Eur. Respir. J. 2016;48(3):768–779.Chappe V., Hinkson D.A., Zhu T., Chang X.B., Riordan J.R., Hanrahan J.W. Phosphorylation of protein kinase C sites in NBD1 and the R domain control CFTR channel activation by PKA. J. Physiol. 2003;548(1):39–52.Chappe V., Hinkson D.A., Zhu T., Chang X.B., Riordan J.R., Hanrahan J.W. Phosphorylation of protein kinase C sites in NBD1 and the R domain control CFTR channel activation by PKA. J. Physiol. 2003;548(1):39–52.Ramteke V.D., Tandan S.K., Kumar D., Aruna Devi R., Shukla M.K., Ravi Prakash V. Increased hyperalgesia by 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a chloride channel blocker in crush injury-induced neuropathic pain in rats. Pharmacol. Biochem. Behav. 2009;91(3):417–422.Ramteke V.D., Tandan S.K., Kumar D., Aruna Devi R., Shukla M.K., Ravi Prakash V. Increased hyperalgesia by 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a chloride channel blocker in crush injury-induced neuropathic pain in rats. Pharmacol. Biochem. Behav. 2009;91(3):417–422.Burnell J.M., Kirby W.M. Effectiveness of a new compound, benemid, in elevating serum penicillin concentrations. J. Clin. Invest. 1951;30(7):697–700.Burnell J.M., Kirby W.M. Effectiveness of a new compound, benemid, in elevating serum penicillin concentrations. J. Clin. Invest. 1951;30(7):697–700.Talbott J.H., Bishop C., Norcross B.M., Lockie L.M. The clinical and metabolic effects of benemid in patients with gout. Trans. Assoc. Am. Physicians. 1951;64:372–377.Talbott J.H., Bishop C., Norcross B.M., Lockie L.M. The clinical and metabolic effects of benemid in patients with gout. Trans. Assoc. Am. Physicians. 1951;64:372–377.Silverman W., Locovei S., Dahl G. Probenecid, a gout remedy, inhibits pannexin 1 channels. Am. J. Physiol. - Cell Physiol. 2008;295(3):761–767.Silverman W., Locovei S., Dahl G. Probenecid, a gout remedy, inhibits pannexin 1 channels. Am. J. Physiol. - Cell Physiol. 2008;295(3):761–767.Barone S., Xu J., Zahedi K., Brooks M., Soleimani M. Probenecid pre-treatment downregulates the kidney Cl-/HCO3- exchanger (Pendrin) and potentiates hydrochlorothiazide-induced diuresis. Front. Physiol. 2018;9:849.Barone S., Xu J., Zahedi K., Brooks M., Soleimani M. Probenecid pre-treatment downregulates the kidney Cl-/HCO3- exchanger (Pendrin) and potentiates hydrochlorothiazide-induced diuresis. Front. Physiol. 2018;9:849.Bang S., Kim K.Y., Yoo S., Lee S.H., Hwang S.W. Transient receptor potential V2 expressed in sensory neurons is activated by probenecid. Neurosci. Lett. 2007;425(2):120–125.Bang S., Kim K.Y., Yoo S., Lee S.H., Hwang S.W. Transient receptor potential V2 expressed in sensory neurons is activated by probenecid. Neurosci. Lett. 2007;425(2):120–125.Cloutier M.M. Probenecid affects chloride secretion in canine tracheal epithelium. Am. Rev. Respir. Dis. 1987;135(6):1329–1333.Cloutier M.M. Probenecid affects chloride secretion in canine tracheal epithelium. Am. Rev. Respir. Dis. 1987;135(6):1329–1333.Diena T., Melani R., Caci E., Pedemonte N., Sondo E., Zegarra-Moran O., Galietta L.J.V. Block of CFTR-dependent chloride currents by inhibitors of multidrug resistance-associated proteins. Eur. J. Pharmacol. 2007;560(2–3):127–131.Diena T., Melani R., Caci E., Pedemonte N., Sondo E., Zegarra-Moran O., Galietta L.J.V. Block of CFTR-dependent chloride currents by inhibitors of multidrug resistance-associated proteins. Eur. J. Pharmacol. 2007;560(2–3):127–131.Hanssens L.S., Duchateau J., Casimir G.J. Cftr protein: Not just a chloride channel? Cells. 2021;10(11):2844.Hanssens L.S., Duchateau J., Casimir G.J. Cftr protein: Not just a chloride channel? Cells. 2021;10(11):2844.Sheppard D.N., Welsh M.J. Structure and function of the CFTR chloride channel. Physiolgical Rev. 1999;79(1 Suppl.):23–45.Sheppard D.N., Welsh M.J. Structure and function of the CFTR chloride channel. Physiolgical Rev. 1999;79(1 Suppl.):23–45.McKinney S.E., Peck H.M., Bochey J.M., Byham B.B., Schuchardt G.S., Beyer K.H. Benemid, p-(DI-n-propylsulfamyl)-benzoic acid; toxicologic properties. J. Pharmacol. Exp. Ther. 1951;102(3):208–214.McKinney S.E., Peck H.M., Bochey J.M., Byham B.B., Schuchardt G.S., Beyer K.H. Benemid, p-(DI-n-propylsulfamyl)-benzoic acid; toxicologic properties. J. Pharmacol. Exp. Ther. 1951;102(3):208–214.

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