Bronchodilator aminophylline may induce atrial or less often ventricular arrhythmias. The mechanism of this proarrhythmic side effect has not been fully explained. Modifications of inward rectifier potassium (Kir) currents including IK1 are known to play an important role in arrhythmogenesis; however, no data on the aminophylline effect on these currents have been published. Hence, we tested the effect of aminophylline (3-100 µM) on IK1 in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. A dual steady-state effect of aminophylline was observed; either inhibition or activation was apparent in individual cells during the application of aminophylline at a given concentration. The smaller the magnitude of the control IK1, the more likely the activation of the current by aminophylline and vice versa. The effect was reversible; the relative changes at -50 and -110 mV did not differ. Using IK1 channel population model, the dual effect was explained by the interaction of aminophylline with two different channel populations, the first one being inhibited and the second one being activated. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells could be simulated. We propose that the dual aminophylline effect may be related to the direct and indirect effect of the drug on various Kir2.x subunits forming the homo- and heterotetrameric IK1 channels in a single cell. The observed IK1 changes induced by clinically relevant concentrations of aminophylline might contribute to arrhythmogenesis related to the use of this bronchodilator in clinical medicine.

Department of Paediatric Anaesthesiology and Intensive Care Medicine Faculty of Medicine and University Hospital Brno Masaryk University Černopolní 9 662 63 Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Zobrazit více v PubMed

Zafar Gondal A, Zulfiqar H (2021) Aminophylline. In StatPearls. StatPearls Publishing.

National Collaborating Centre for Chronic Conditions (2004) Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 59:1–232

Mahemuti G, Zhang H, Li J, Tieliwaerdi N, Ren L (2018) Efficacy and side effects of intravenous theophylline in acute asthma: a systematic review and meta-analysis. Drug Des Devel Ther 12:99–120. https://doi.org/10.2147/DDDT.S156509 PubMed DOI PMC

Saint GL, Semple MG, Sinha I, Hawcutt DB (2018) Optimizing the dosing of intravenous theophylline in acute severe asthma in children. Paediatr Drugs 20:209–214. https://doi.org/10.1007/s40272-017-0281-x PubMed DOI PMC

Cooney L, Sinha I, Hawcutt D (2016) Aminophylline dosage in asthma exacerbations in children: a systematic review. PLoS ONE 11:e0159965. https://doi.org/10.1371/journal.pone.0159965 PubMed DOI PMC

Neame M, Aragon O, Fernandes RM, Sinha I (2015) Salbutamol or aminophylline for acute severe asthma: how to choose which one, when and why? Arch Dis Child Educ Pract Ed 100:215–222. https://doi.org/10.1136/archdischild-2014-306186 PubMed DOI

Ye C, Miao C, Yu L, Dong Z, Zhang J, Mao Y, Lu X, Lyu Q (2019) Factors affecting the efficacy and safety of aminophylline in treatment of apnea of prematurity in neonatal intensive care unit. Pediatr Neonatol 60:43–49. https://doi.org/10.1016/j.pedneo.2018.03.008 PubMed DOI

Abidov A, Dilsizian V, Doukky R, Duvall WL, Dyke C, Elliott MD, Hage FG, Henzlova MJ, Johnson NP, Schwartz RG, Thomas GS, Einstein AJ (2019) Aminophylline shortage and current recommendations for reversal of vasodilator stress: an ASNC information statement endorsed by SCMR. J Nucl Cardiol 26:1007–1014. https://doi.org/10.1007/s12350-018-01548-0 PubMed DOI

Chazan R, Karwat K, Tyminska K, Tadeusiak W, Droszcz W (1995) Cardiac arrhythmias as a result of intravenous infusions of theophylline in patients with airway obstruction. Int J Clin Pharmacol Ther 33:170–175 PubMed

Varriale P, Ramaprasad S (1993) Aminophylline induced atrial fibrillation. Pacing Clin Electrophysiol 16:1953–1955. https://doi.org/10.1111/j.1540-8159.1993.tb00987.x PubMed DOI

Hendeles L, Bighley L, Richardson RH, Hepler CD, Carmichael J (2006) Frequent toxicity from IV aminophylline infusions in critically ill patients. Ann Pharmacother 40:1417–1423. https://doi.org/10.1345/aph.140027 PubMed DOI

Paloucek FP, Rodvold KA (1988) Evaluation of theophylline overdoses and toxicities. Ann Emerg Med 17:135–144. https://doi.org/10.1016/s0196-0644(88)80299-3 PubMed DOI

Patel AK, Skatrud JB, Thomsen JH (1981) Cardiac arrhythmias due to oral aminophylline in patients with chronic obstructive pulmonary disease. Chest 80:661–665. https://doi.org/10.1378/chest.80.6.661 PubMed DOI

Tamargo J, Caballero R, Delpón E (2012) Drug-induced atrial fibrillation. Expert Opin Drug Saf 11:615–634. https://doi.org/10.1517/14740338.2012.698609 PubMed DOI

Komadina KH, Carlson TA, Strollo PJ, Navratil DL (1992) Electrophysiologic study of the effects of aminophylline and metaproterenol on canine myocardium. Chest 101:232–238. https://doi.org/10.1378/chest.101.1.232 PubMed DOI

Beaumont J, Davidenko N, Davidenko JM, Jalife J (1998) Spiral waves in two-dimensional models of ventricular muscle: formation of a stationary core. Biophys J 75:1–14. https://doi.org/10.1016/S0006-3495(98)77490-9 PubMed DOI PMC

Enriquez A, Frankel DS, Baranchuk A (2017) Pathophysiology of ventricular tachyarrhythmias: from automaticity to reentry. Herzschrittmacherther Elektrophysiol 28:149–156. https://doi.org/10.1007/s00399-017-0512-4 PubMed DOI

Heijman J, Guichard JB, Dobrev D, Nattel S (2018) Translational challenges in atrial fibrillation. Circ Res 122:752–773. https://doi.org/10.1161/CIRCRESAHA.117.311081 PubMed DOI

Jalife J (2016) Dynamics and molecular mechanisms of ventricular fibrillation in structurally normal hearts. Card Electrophysiol Clin 8:601–612. https://doi.org/10.1016/j.ccep.2016.04.009 PubMed DOI

Šimurda J, Šimurdová M, Bébarová M (2018) Inward rectifying potassium currents resolved into components: modeling of complex drug actions. Pflugers Arch 470:315–325. https://doi.org/10.1007/s00424-017-2071-2 PubMed DOI

Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J (2014) Dual effect of ethanol on inward rectifier potassium current I PubMed

Bosch RF, Li GR, Gaspo R, Nattel S (1999) Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes. J Pharmacol Exp Ther 289:156–165 PubMed

Ogura T, Shuba LM, McDonald TF (1995) Action potentials, ionic currents and cell water in guinea pig ventricular preparations exposed to dimethyl sulfoxide. J Pharmacol Exp Ther 273:1273–1286 PubMed

Šimurda J, Šimurdová M, Bébarová M (2019) The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: insight from a quantitative model. PLoS ONE 14:e0223448. https://doi.org/10.1371/journal.pone.0223448 PubMed DOI PMC

Caballero R, Dolz-Gaitón P, Gómez R, Amorós I, Barana A, González de la Fuente M, Osuna L, Duarte J, López-Izquierdo A, Moraleda I, Gálvez E, Sánchez-Chapula JA, Tamargo J, Delpón E (2010) Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine induced rectification. Proc Natl Acad Sci USA 107:15631–15636. https://doi.org/10.1073/pnas.1004021107 PubMed DOI PMC

Gómez R, Caballero R, Barana A, Amorós I, DePalm SH, Matamoros M, Núñez M, Pérez-Hernández M, Iriepa I, Tamargo J, Delpón E (2014) Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents. Cardiovasc Res 104:337–346. https://doi.org/10.1093/cvr/cvu203 PubMed DOI

Liu GX, Derst C, Schlichthorl G, Heinen S, Seebohm G, Bruggemann A, Kummer W, Veh RW, Daut J, Preisig-Muller R (2001) Comparison of cloned Kir2 channels with native inward rectifier K PubMed DOI

López-Izquierdo A, Aréchiga-Figueroa IA, Moreno-Galindo EG, Ponce-Balbuena D, Rodríguez-Martínez M, Ferrer-Villada T, Rodríguez-Menchaca AA, van der Heyden MAG, Sánchez-Chapula JA (2011) Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP PubMed DOI

Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291–366. https://doi.org/10.1152/physrev.00021.2009 PubMed DOI

Zaritsky JJ, Redell JB, Tempel BL, Schwarz TL (2001) The consequences of disrupting cardiac inwardly rectifying K+ current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol 533:697–710. https://doi.org/10.1111/j.1469-7793.2001.t01-1-00697.x PubMed DOI PMC

Zhang L, Liu Q, Liu C, Zhai X, Feng Q, Xu R, Cui X, Zhao Z, Cao J, Wu B (2013) Zacopride selectively activates the Kir2.1 channel via a PKA signaling pathway in rat cardiomyocytes. Sci China Life Sci 56:788–796. https://doi.org/10.1007/s11427-013-4531-z PubMed DOI

Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, Demolombe S (2007) Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 582:675–693. https://doi.org/10.1113/jphysiol.2006.126714 PubMed DOI PMC

Koumi S, Backer CL, Arentzen CE, Sato R (1995) Beta-adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts. J Clin Invest 96:2870–2881. https://doi.org/10.1172/JCI118358 PubMed DOI PMC

Koumi S, Wasserstrom JA, Ten Eick RE (1995) Beta-adrenergic and cholinergic modulation of inward rectifier K+ channel function and phosphorylation in Guinea-pig ventricle. J Physiol 486:661–678. https://doi.org/10.1113/jphysiol.1995.sp020842 PubMed DOI PMC

Sessler CN, Cohen MD (1990) Cardiac arrhythmias during theophylline toxicity. A prospective continuous electrocardiographic study. Chest 98:672–678. https://doi.org/10.1378/chest.98.3.672 PubMed DOI

Vestal RE, Eiriksson CE Jr, Musser B, Ozaki LK, Halter JB (1983) Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 67:162–171. https://doi.org/10.1161/01.cir.67.1.162 PubMed DOI

Ichikawa K, Wada T, Nishihara T, Tsuji M, Mori A, Yokohama F, Hasegawa D, Kawamoto K, Tanakaya M, Katyama Y, Sakuragi S, Ito H (2017) A case of life-threatening supraventricular tachycardia storm associated with theophylline toxicity. J Cardiol Cases 15:125–128. https://doi.org/10.1016/j.jccase.2016.12.004 PubMed DOI PMC

Ravens U, Cerbai E (2008) Role of potassium currents in cardiac arrhythmias. Europace 10:1133–1137. https://doi.org/10.1093/europace/eun193 PubMed DOI

Cubeddu LX (2016) Drug-induced inhibition and trafficking disruption of ion channels: pathogenesis of QT abnormalities and drug-induced fatal arrhythmias. Curr Cardiol Rev 12:141–154. https://doi.org/10.2174/1573403x12666160301120217 PubMed DOI PMC

Dhamoon AS, Jalife J (2005) The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm 2:316–324. https://doi.org/10.1016/j.hrthm.2004.11.012 PubMed DOI

Zhang Z, Liu MB, Huang X, Song Z, Qu Z (2021) Mechanisms of premature ventricular complexes caused by QT prolongation. Biophys J 120:352–369. https://doi.org/10.1016/j.bpj.2020.12.001 PubMed DOI

Noujaim SF, Pandit SV, Berenfeld O, Vikstrom K, Cerrone M, Mironov S, Zugermayr M, Lopatin AN, Jalife J (2007) Up-regulation of the inward rectifier K+ current (IK1) in the mouse heart accelerates and stabilizes rotors. J Physiol 578(1):315–326. https://doi.org/10.1113/jphysiol.2006.121475 PubMed DOI

Vaquero M, Calvo D, Jalife J (2008) Cardiac fibrillation: from ion channels to rotors in the human heart. Heart Rhythm 5:872–879. https://doi.org/10.1016/j.hrthm.2008.02.034 PubMed DOI PMC

Adeniran I, El Harchi A, Hancox JC, Zhang H (2012) Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling. Cardiovasc Res 94:66–76. https://doi.org/10.1093/cvr/cvs082 PubMed DOI

Bodhinathan K, Slesinger PA (2013) Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. Proc Natl Acad Sci USA 110:18309–18314. https://doi.org/10.1073/pnas.1311406110 PubMed DOI PMC

Hořáková Z, Matejovič P, Pásek M, Hošek J, Šimurdová M, Šimurda J, Bébarová M (2016) Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current I PubMed

Salbutamol attenuates arrhythmogenic effect of aminophylline in a hPSC-derived cardiac model