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Published in: Journal of Interventional Cardiac Electrophysiology 3/2021

01-04-2021 | Diabetic Cardiomyopathy

Electrocardiological effects of ranolazine and lidocaine on normal and diabetic rat atrium

Authors: Hajar Khazraei, Hossein Mirkhani, Waheed Shabbir

Published in: Journal of Interventional Cardiac Electrophysiology | Issue 3/2021

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Abstract

Purpose

Cellular changes occurring in diabetic cardiomyopathy include disturbances of calcium and sodium homeostasis. Voltage-gated sodium channels are responsible for the initiation of cardiac action potentials, and the excitability would create relevance. The effect of ranolazine as a sodium channel blocker on atrium electromechanical parameters is investigated and compared with lidocaine in streptozocin-treated diabetic rats.

Methods

After an 8-week induction of diabetes type I, the effect of cumulative concentrations of ranolazine and lidocaine on the electrophysiology of isolated atrium was studied. Ranolazine’s effects were evaluated on cardiac sodium current in normal- and high-glucose medium, with whole-cell patch-clamp technique.

Results

Ranolazine at therapeutic concentrations had no significant statistical effect on refractory period in normal and diabetic isolated heart. Ranolazine (10 μM) caused a hyperpolarizing shift of V1/2 for steady-state inactivation in normal media, while it significantly elicited a depolarizing shift in high-glucose media (p < 0.05).

Conclusion

It is concluded that in the isolated rat atrium preparation, ranolazine and lidocaine have no beneficial on diabetic cardiomyopathy. Although refractoriness and contractility were not much different in normal and diabetic atria, there was a definite effect of ranolazine and lidocaine on sodium current in varying concentrations. This may have significance in future therapeutics.
Literature
1.
go back to reference Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 2010;375:1212–23.CrossRef Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 2010;375:1212–23.CrossRef
2.
go back to reference Undrovinas NA, Maltsev VA, Belardinelli L, Sabbah HN, Undrovinas A. Late sodium current contributes to diastolic cell ca2+ accumulation in chronic heart failure. J Physiol Sci. 2010;60:245–57.CrossRef Undrovinas NA, Maltsev VA, Belardinelli L, Sabbah HN, Undrovinas A. Late sodium current contributes to diastolic cell ca2+ accumulation in chronic heart failure. J Physiol Sci. 2010;60:245–57.CrossRef
3.
go back to reference Burashnikov A, Antzelevitch C. Atrial-selective sodium channel blockers: do they exist? J Cardiovasc Pharmacol. 2008;52:121–8.CrossRef Burashnikov A, Antzelevitch C. Atrial-selective sodium channel blockers: do they exist? J Cardiovasc Pharmacol. 2008;52:121–8.CrossRef
4.
go back to reference Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias, and diabetes. Pharmacol Ther. 2012;133:311–23.CrossRef Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias, and diabetes. Pharmacol Ther. 2012;133:311–23.CrossRef
5.
go back to reference Casis O, Gallego M, Iriarte M, Sanchez-Chapula JA. Effects of diabetic cardiomyopathy on regional electrophysiologic characteristics of rat ventricle. Diabetologia. 2000;43:101–9.CrossRef Casis O, Gallego M, Iriarte M, Sanchez-Chapula JA. Effects of diabetic cardiomyopathy on regional electrophysiologic characteristics of rat ventricle. Diabetologia. 2000;43:101–9.CrossRef
6.
go back to reference Bilginoglu A, Kandilci HB, Turan B. Intracellular levels of Na(+) and TTX-sensitive Na(+) channel current in diabetic rat ventricular cardiomyocytes. Cardiovasc Toxicol. 2013;13:138–47.CrossRef Bilginoglu A, Kandilci HB, Turan B. Intracellular levels of Na(+) and TTX-sensitive Na(+) channel current in diabetic rat ventricular cardiomyocytes. Cardiovasc Toxicol. 2013;13:138–47.CrossRef
7.
go back to reference Soliman D, Wang L, Hamming KSC, Yang W, Fatehi M, Carter CC, et al. Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia- and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange. J Pharmacol Exp Ther. 2012;343:325–32.CrossRef Soliman D, Wang L, Hamming KSC, Yang W, Fatehi M, Carter CC, et al. Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia- and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange. J Pharmacol Exp Ther. 2012;343:325–32.CrossRef
8.
go back to reference Luan R, Liu S, Yin T, Lau WB, Wang Q, Guo W, et al. High glucose sensitizes adult cardiomyocytes to ischaemia/reperfusion injury through nitrative thioredoxin inactivation. Cardiovasc Res. 2009;83:294–302.CrossRef Luan R, Liu S, Yin T, Lau WB, Wang Q, Guo W, et al. High glucose sensitizes adult cardiomyocytes to ischaemia/reperfusion injury through nitrative thioredoxin inactivation. Cardiovasc Res. 2009;83:294–302.CrossRef
9.
go back to reference D’Amico M, Marfella R, Nappo F, Di Filippo C, De Angelis L, Berrino L, et al. High glucose induces ventricular instability and increases vasomotor tone in rats. Diabetologia. 2001;44:464.CrossRef D’Amico M, Marfella R, Nappo F, Di Filippo C, De Angelis L, Berrino L, et al. High glucose induces ventricular instability and increases vasomotor tone in rats. Diabetologia. 2001;44:464.CrossRef
10.
go back to reference Bich-Hoai TT, Marin A, Dinu C, Banciu D, Maria-Luiza F, Ristoiu V. Hypoxia and high glucose activate tetrodotoxin-resistant Na+ currents through PKA and PKC. Acta Neurobiol Exp. 2010;70:351–61. Bich-Hoai TT, Marin A, Dinu C, Banciu D, Maria-Luiza F, Ristoiu V. Hypoxia and high glucose activate tetrodotoxin-resistant Na+ currents through PKA and PKC. Acta Neurobiol Exp. 2010;70:351–61.
11.
go back to reference Rajamani S, El-Bizri N, Shryock JC, Makielski JC, Belardinelli L. Use-dependent block of cardiac late Na+ current by Ranolazine. Heart Rhythm. 2009;6:1625–31.CrossRef Rajamani S, El-Bizri N, Shryock JC, Makielski JC, Belardinelli L. Use-dependent block of cardiac late Na+ current by Ranolazine. Heart Rhythm. 2009;6:1625–31.CrossRef
12.
go back to reference El-Menyar AA. Dysrhythmia and electrocardiographic changes in diabetes mellitus: pathophysiology and impact on the incidence of sudden cardiac death. J Cardiovasc Med. 2006;7:580–5.CrossRef El-Menyar AA. Dysrhythmia and electrocardiographic changes in diabetes mellitus: pathophysiology and impact on the incidence of sudden cardiac death. J Cardiovasc Med. 2006;7:580–5.CrossRef
13.
go back to reference Warley A. Changes in sodium concentration in cardiac myocytes from diabetic rats. Scanning Microsc. 1991;5:239–44 discussion 244-5.PubMed Warley A. Changes in sodium concentration in cardiac myocytes from diabetic rats. Scanning Microsc. 1991;5:239–44 discussion 244-5.PubMed
14.
go back to reference Katoh H, Noda N, Hayashi H, Satoh H, Terada H, Ohno R, et al. Intracellular sodium concentration in diabetic rat ventricular myocytes. Jpn Heart J. 1995;36:647–56.CrossRef Katoh H, Noda N, Hayashi H, Satoh H, Terada H, Ohno R, et al. Intracellular sodium concentration in diabetic rat ventricular myocytes. Jpn Heart J. 1995;36:647–56.CrossRef
15.
go back to reference Pierce GN, Ramjiawan B, Dhalla NS, Ferrari R. Na(+)-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats. Am J Phys. 1990;258(1 Pt 2):H255–61. Pierce GN, Ramjiawan B, Dhalla NS, Ferrari R. Na(+)-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats. Am J Phys. 1990;258(1 Pt 2):H255–61.
16.
go back to reference Otake H, Suzuki H, Honda T, Maruyama Y. Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart. Int Heart J. 2009;50:627–41.CrossRef Otake H, Suzuki H, Honda T, Maruyama Y. Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart. Int Heart J. 2009;50:627–41.CrossRef
17.
go back to reference Watanabe M, Yokoshiki H, Mitsuyama H, Mizukami K, Ono T, Tsutsui H. Conduction and refractory disorders in the diabetic atrium. Am J Physiol Heart CircPhysiol. 2012;303:H86–95.CrossRef Watanabe M, Yokoshiki H, Mitsuyama H, Mizukami K, Ono T, Tsutsui H. Conduction and refractory disorders in the diabetic atrium. Am J Physiol Heart CircPhysiol. 2012;303:H86–95.CrossRef
18.
go back to reference Savabi F, Kirsch A. Altered functional activity and anoxic tolerance in diabetic rat isolated atria. Arch Biochem Biophys. 1990;279:183–7.CrossRef Savabi F, Kirsch A. Altered functional activity and anoxic tolerance in diabetic rat isolated atria. Arch Biochem Biophys. 1990;279:183–7.CrossRef
19.
go back to reference Stables CL, Musa H, Mitra A, Bhushal S, Deo M, Guerrero-Serna G, et al. Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle. J Mol Cell Cardiol. 2014;69:24–31.CrossRef Stables CL, Musa H, Mitra A, Bhushal S, Deo M, Guerrero-Serna G, et al. Reduced Na+ current density underlies impaired propagation in the diabetic rabbit ventricle. J Mol Cell Cardiol. 2014;69:24–31.CrossRef
20.
go back to reference Bracken NK, Woodall AJ, Howarth FC, Singh J. Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes. Mol Cell Biochem. 2004;261:235–43.CrossRef Bracken NK, Woodall AJ, Howarth FC, Singh J. Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes. Mol Cell Biochem. 2004;261:235–43.CrossRef
21.
go back to reference Khazraei H, Mirkhani H, Purkhosrow A. Vasorelaxant effect of ranolazine on isolated normal and diabetic rat aorta: a study of possible mechanisms. Acta Physiol Hung. 2013;100:153–62.CrossRef Khazraei H, Mirkhani H, Purkhosrow A. Vasorelaxant effect of ranolazine on isolated normal and diabetic rat aorta: a study of possible mechanisms. Acta Physiol Hung. 2013;100:153–62.CrossRef
22.
go back to reference Khazraei H, Shafa M, Mirkhani H. Effect of ranolazine on cardiac microcirculation in normal and diabetic rats. Acta Physiol Hung. 2014;101:301–8.CrossRef Khazraei H, Shafa M, Mirkhani H. Effect of ranolazine on cardiac microcirculation in normal and diabetic rats. Acta Physiol Hung. 2014;101:301–8.CrossRef
23.
go back to reference Khazraei H, Mirkhani H, Akmali M. The antianginal agent ranolazine inhibits mitochondrial β-oxidation pathway. Clin Exp Pharmacol. 2016;6:2. Khazraei H, Mirkhani H, Akmali M. The antianginal agent ranolazine inhibits mitochondrial β-oxidation pathway. Clin Exp Pharmacol. 2016;6:2.
24.
go back to reference Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW, et al. Defective intracellular Ca+2 signalling contribute to cardiomyopathy in type I diabetic rats. Am J Physiol Heart Circ Physiol. 2002;283:H1398–408.CrossRef Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW, et al. Defective intracellular Ca+2 signalling contribute to cardiomyopathy in type I diabetic rats. Am J Physiol Heart Circ Physiol. 2002;283:H1398–408.CrossRef
25.
go back to reference Dillmann WH. Overexpression of sarcoplasmic reticulum Ca+2-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes. 2002;51:1166–71.CrossRef Dillmann WH. Overexpression of sarcoplasmic reticulum Ca+2-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes. 2002;51:1166–71.CrossRef
26.
go back to reference Howarth FC, Jacobson M, Qureshi MA. Altered gene expression may underlie prolonged duration of the QT interval and ventricular action potential in streptozotocin-induced diabetic rat heart. Mol Cell Biochem. 2009;328:57–65.CrossRef Howarth FC, Jacobson M, Qureshi MA. Altered gene expression may underlie prolonged duration of the QT interval and ventricular action potential in streptozotocin-induced diabetic rat heart. Mol Cell Biochem. 2009;328:57–65.CrossRef
Metadata
Title
Electrocardiological effects of ranolazine and lidocaine on normal and diabetic rat atrium
Authors
Hajar Khazraei
Hossein Mirkhani
Waheed Shabbir
Publication date
01-04-2021
Publisher
Springer US
Published in
Journal of Interventional Cardiac Electrophysiology / Issue 3/2021
Print ISSN: 1383-875X
Electronic ISSN: 1572-8595
DOI
https://doi.org/10.1007/s10840-020-00742-w

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