Mechanical effects of ranolazine on normal and diabetic-isolated rat heart

Hajar Khazraei , Masoumeh Akmali, Hossein Mirkhani

Abstract


Background and purpose: Diabetic cardiomyopathy is a complication of diabetes defined as cardiac dysfunction without the involvement of pericardial vessels, hypertension, or cardiac valve disorders. Ranolazine, an antianginal drug, acts through blocking of cardiac late sodium channels and/or inhibiting beta-oxidation of fatty acids. With regard to its mechanism of action, the present work has been carried out to investigate the potential useful effects of ranolazine on the systolic and diastolic dysfunctions in an experimental rat model of diabetic cardiomyopathy. Lidocaine, as a sodium channel blocker, was used to have a clearer image of the involved mechanisms.

Experimental approach: Diabetes was induced by streptozocin. After 8 weeks, the effects of cumulative concentrations of ranolazine and lidocaine were evaluated on diabetic and normal hearts by the Langendorff method. Finally, the hearts were isolated from the Langendorff system and adenosine three phosphates (ATP) and adenosine diphosphate (ADP) concentrations were measured to assay the metabolic effect of ranolazine.

Findings/Results: Ranolazine significantly decreased the velocity of systolic contraction (+dP/dt) and the velocity of diastolic relaxation (-dP/dt) and developed pressure in normal and diabetic rat hearts. However, this negative effect was greater in normal hearts compared to diabetics. Ranolazine (100 µM) decreased the ATP level only in normal hearts and the ATP/ADP ratio decreased significantly (P < 0.05) in both groups. This reduction was more prominent in normal hearts.

Conclusion and implications: It is concluded that in the isolated rat heart preparation, ranolazine has no benefit on diabetic cardiomyopathy and may even worsen it. It seems that these effects are related to the metabolic effects of ranolazine.


Keywords


Diabetes; Langendorff isolated heart system; Lidocaine; Ranolazine.

Full Text:

PDF

References


Motamedrad M, Shokouhifar A, Hemmati M, Moossavi M. The regulatory effect of saffron stigma on the gene expression of the glucose metabolism key enzymes and stress proteins in streptozotocin-induced diabetic rats. Res Pharm Sci. 2019;14(3):255-262.

DOI: 10.4103/1735-5362.258494.

Ofstad AP. Myocardial dysfunction and cardiovascular disease in type 2 diabetes. Scand J Clin Lab Invest. 2016;76(4):271-281.

DOI: 10.3109/00365513.2016.1155230.

Chong CR, Clarke K, Levelt E. Metabolic remodelling in diabetic cardiomyopathy. Cardiovasc Res. 2017;113(4):422-430.

DOI: 10.1093/cvr/cvx018.

Rayner-Hartley E, Sedlak T. Ranolazine: a contemporary review. J Am Heart Assoc. 2016;5(3):e003196,1-8.

DOI: 10.1161/JAHA.116.003196.

Sabbah HN, Chandler MP, Mishima T, Suzuki G, Chaudhry P, Nass O, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail. 2002;8(6):416-422.

DOI: 10.1054/jcaf.2002.129232.

Le DE, Davis CM, Wei K, Zhao Y, Cao Z, Nugent M, et al. Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels. Am J Physiol Heart Circ Physiol. 2020;318(1):H189-H202.

DOI: 10.1152/ajpheart.00217.2019.

Dalal JJ, Mishra S. Modulation of myocardial energetics: an important category of agents in the multimodal treatment of coronary artery disease and heart failure. Indian Heart J. 2017;69(3):393-401.

DOI: 10.1016/j.ihj.2017.04.001.

Khazraei H, Mirkhani H, Shabbir W. Electrocardiological effects of ranolazine and lidocaine on normal and diabetic rat atrium. J Interv Card Electrophysiol. 2020;1-6.

DOI: 10.1007/s10840-020-00742-w.

Jungen C, Scherschel K, Bork NI, Kuklik P, Eickholt C, Kniep H, et al. Impact of intracardiac neurons on cardiac electrophysiology and arrhythmogenesis in an ex vivo langendorff system. J Vis Exp. 2018;135:e57617,1-8.

DOI: 10.3791/57617.

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(2):153-162.

DOI: 10.1556/APhysiol.100.2013.2.3.

Khazraei H, Mirkhani H, Akmali M. The antianginal agent ranolazine inhibits mitochondrial β-oxidation pathway. J Clin Exp Pharmacol. 2016;6(2):1000203,1-4.

DOI: 10.4172/2161-1459.1000203.

Parikh MC, Patel SN, Shen Y, Lau-Cam CA. Role of taurine on the actions of alcohol against systemic and cardiac biochemical changes in the diabetic rat. Adv Exp Med Biol. 2015;803:313-338.

DOI: 10.1007/978-3-319-15126-7_25.

Mahalakshmi A, Kurian GA. Mitochondrial dysfunction plays a key role in the abrogation of cardioprotection by sodium hydrosulfide post-conditioning in diabetic cardiomyopathy rat heart. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(3):339-348.

DOI: 10.1007/s00210-019-01733-z.

Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res. 2010;88(2):229-240.

DOI: 10.1093/cvr/cvq239.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.