Ranolazine exerts atrial antiarrhythmic effects in a rat model of monocrotaline-induced pulmonary hypertension.
arrhythmia
monocrotaline
pulmonary hypertension
ranolazine
right atrium
Journal
Basic & clinical pharmacology & toxicology
ISSN: 1742-7843
Titre abrégé: Basic Clin Pharmacol Toxicol
Pays: England
ID NLM: 101208422
Informations de publication
Date de publication:
May 2023
May 2023
Historique:
revised:
10
02
2023
received:
22
11
2022
accepted:
13
02
2023
medline:
6
4
2023
pubmed:
18
2
2023
entrez:
17
2
2023
Statut:
ppublish
Résumé
Atrial arrhythmias are a hallmark of heart diseases. The antiarrhythmic drug ranolazine with multichannel blocker properties is a promising agent to treat atrial arrhythmias. We therefore used the rat model of monocrotaline-induced pulmonary-hypertension to assess whether ranolazine can reduce the incidence of ex vivo atrial arrhythmias in isolated right atrium. Four-week-old Wistar rats were injected with 50 mg/kg of monocrotaline, and isolated right atrium function was studied 14 days later. The heart developed right atrium and right ventricular hypertrophy, and the ECG showed an increased P wave duration and QT interval, which are markers of the disease. Moreover, monocrotaline injection caused enhanced chronotropism and faster kinetics of contraction and relaxation in isolated right atrium. Additionally, in a concentration-dependent manner, ranolazine showed chronotropic and ionotropic effects upon isolated right atrium, with higher potency in the control when compared with experimental model. Using a burst pacing protocol, the isolated right atrium from the monocrotaline-treated animals was more susceptible to develop arrhythmias, and ranolazine was able to attenuate the phenotype. Thus, we concluded that the rat model of monocrotaline-induced pulmonary-hypertension develops right atrium remodelling, which increased the susceptibility to present ex vivo atrial arrhythmias, and the antiarrhythmic drug ranolazine ameliorated the phenotype.
Substances chimiques
Ranolazine
A6IEZ5M406
Anti-Arrhythmia Agents
0
Monocrotaline
73077K8HYV
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
359-368Subventions
Organisme : FAPESP
ID : 2019/21304-4
Organisme : FAPESP
ID : 2021/05584-7
Organisme : CNPq
ID : 304257/2020-6
Informations de copyright
© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.
Références
Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi:10.1016/S0140-6736(18)32279-7
Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736-1788. doi:10.1016/S0140-6736(18)32203-7
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. Feb 1, 2021;42(5):373-498. doi:10.1093/eurheartj/ehaa612
Hong L, Zhang M, Ly OT, et al. Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation. Stem Cell Reports. 2021;16(6):1542-1554. doi:10.1016/j.stemcr.2021.04.019
Ramos-Mondragon R, Edokobi N, Hodges SL, et al. Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation. JCI. Insight. 2022;7(10). doi:10.1172/jci.insight.152050
Scirica BM, Morrow DA, Hod H, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116(15):1647-1652. doi:10.1161/CIRCULATIONAHA.107.724880
Hiram R, Naud P, Xiong F, et al. Right atrial mechanisms of atrial fibrillation in a rat model of right heart disease. J am Coll Cardiol. 2019;74(10):1332-1347. doi:10.1016/j.jacc.2019.06.066
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. Oct 11, 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237
Nogueira-Ferreira R, Vitorino R, Ferreira R, Henriques-Coelho T. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: a network approach. Pulm Pharmacol Ther. 2015;35:8-16. doi:10.1016/j.pupt.2015.09.007
Wilson DW, Segall HJ, Pan LC, Lame MW, Estep JE, Morin D. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5-6):307-325. doi:10.3109/10408449209146311
Henkens IR, Mouchaers KT, Vliegen HW, et al. Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography. Am J Physiol Heart Circ Physiol. Aug 2007;293(2):H1300-H1307. doi:10.1152/ajpheart.01359.2006
Handoko ML, de Man FS, Happe CM, et al. Opposite effects of training in rats with stable and progressive pulmonary hypertension. Circulation. 2009;120(1):42-49. doi:10.1161/CIRCULATIONAHA.108.829713
Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110(8):904-910. doi:10.1161/01.cir.0000139333.83620.5d
Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation. 2007;116(13):1449-1457. doi:10.1161/CIRCULATIONAHA.107.704890
Opacic D, van Hunnik A, Zeemering S, et al. Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation. Heart Rhythm. 2021;18(4):615-622. doi:10.1016/j.hrthm.2020.11.021
Sossalla S, Kallmeyer B, Wagner S, et al. Altered Na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J am Coll Cardiol. 2010;55(21):2330-2342. doi:10.1016/j.jacc.2009.12.055
McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation. 1996;93(1):135-142. doi:10.1161/01.cir.93.1.135
Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, Lykkesfeldt J. BCPT policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol. 2021;128(1):4-8. doi:10.1111/bcpt.13492
Fulton RM, Hutchinson EC, Jones AM. Ventricular weight in cardiac hypertrophy. Br Heart J. 1952;14(3):413-420. doi:10.1136/hrt.14.3.413
Teixeira-Fonseca JL, Santos-Miranda A, da Silva JB, et al. Eugenol interacts with cardiac sodium channel and reduces heart excitability and arrhythmias. Life Sci. 2021;282:119761. doi:10.1016/j.lfs.2021.119761
Zafalon N Jr, Bassani JW, Bassani RA. Cholinergic-adrenergic antagonism in the induction of tachyarrhythmia by electrical stimulation in isolated rat atria. J Mol Cell Cardiol. 2004;37(1):127-135. doi:10.1016/j.yjmcc.2004.04.020
Liang F, Fan P, Jia J, et al. Inhibitions of late INa and CaMKII act synergistically to prevent ATX-II-induced atrial fibrillation in isolated rat right atria. J Mol Cell Cardiol. 2016;94:122-130. doi:10.1016/j.yjmcc.2016.04.001
Ghebleh Zadeh N, Vaezi G, Bakhtiarian A, Mousavi Z, Shiravi A, Nikoui V. The potassium channel blocker, dalfampridine diminishes ouabain-induced arrhythmia in isolated rat atria. Arch Physiol Biochem. 2019;125(1):25-29. doi:10.1080/13813455.2018.1430158
Lambert M, Boet A, Rucker-Martin C, et al. Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension. Cardiovasc Res. 2018;114(6):880-893. doi:10.1093/cvr/cvy016
Antigny F, Hautefort A, Meloche J, et al. Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation. 2016;133(14):1371-1385. doi:10.1161/CIRCULATIONAHA.115.020951
Rocchetti M, Sala L, Rizzetto R, et al. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovasc Res. 2014;104(1):37-48. doi:10.1093/cvr/cvu188
Liles JT, Hoyer K, Oliver J, Chi L, Dhalla AK, Belardinelli L. Ranolazine reduces remodeling of the right ventricle and provoked arrhythmias in rats with pulmonary hypertension. J Pharmacol Exp Ther. 2015;353(3):480-489. doi:10.1124/jpet.114.221861
Wu J, Cheng L, Lammers WJ, et al. Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine. Prog Biophys Mol Biol. 2008;98(2-3):198-207. doi:10.1016/j.pbiomolbio.2009.01.003
Gomez-Arroyo JG, Farkas L, Alhussaini AA, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 2012;302(4):L363-L369. doi:10.1152/ajplung.00212.2011
Kawade A, Yamamura A, Fujiwara M, et al. Comparative analysis of age in monocrotaline-induced pulmonary hypertensive rats. J Pharmacol Sci. 2021;147(1):81-85. doi:10.1016/j.jphs.2021.05.012
Lookin O, Mukhlynina E, Protsenko Y. Contractile behavior of right atrial myocardium of healthy rats and rats with the experimental model of pulmonary hypertension. Int J Mol Sci. 2022;23(8):4186. doi:10.3390/ijms23084186
Chu Y, Yang Q, Ren L, et al. Late sodium current in atrial cardiomyocytes contributes to the induced and spontaneous atrial fibrillation in rabbit hearts. J Cardiovasc Pharmacol. 2020;76(4):437-444. doi:10.1097/FJC.0000000000000883
Horvath B, Hezso T, Kiss D, et al. Late sodium current inhibitors as potential antiarrhythmic agents. Front Pharmacol. 2020;11:413. doi:10.3389/fphar.2020.00413
Khan SS, Cuttica MJ, Beussink-Nelson L, et al. Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ. 2015;5(3):547-556. doi:10.1086/682427
Smith B, Genuardi MV, Koczo A, et al. Atrial arrhythmias are associated with increased mortality in pulmonary arterial hypertension. Pulm Circ. 2018;8(3):2045894018790316. doi:10.1177/2045894018790316
Cannillo M, Grosso Marra W, Gili S, et al. Supraventricular arrhythmias in patients with pulmonary arterial hypertension. Am J Cardiol. 2015;116(12):1883-1889. doi:10.1016/j.amjcard.2015.09.039