Beyond angina: Ranolazine is associated with increased forced-swimming endurance and altered echocardiographic parameters in healthy rats: a comparative study with Trimetazidine
6 affiliations
- 1Department of Cardiology, Ministry of Health Çorlu State Hospital, Zafer, Bülent Ecevit Cd. 4 A, Çorlu, Tekirdağ, 59850 Türkiye
- 2Liv Hospital Vadiistanbul, Sarıyer, Istanbul, Türkiye
- 3Veterinary Clinic, Health Sciences University Hamidiye Experimental Animals Laboratory, Istanbul, Türkiye
- 4Department of Cardiology, Ministry of Health İzmir Bayraklı City Hospital, Bayraklı, İzmir, Türkiye
- 5Department of Internal Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD USA
- 6Department of Cardiology, Health Sciences University Sultan 2. Abdülhamid Han Training and Research Hospital, Üsküdar, Istanbul, Türkiye
Abstract
Background: Anti-anginal agents that modulate myocardial substrate metabolism, such as ranolazine and trimetazidine, are pharmacologically capable of altering exercise performance independently of their licensed indication in ischemic heart disease. Trimetazidine has been included on the World Anti-Doping Agency (WADA) Prohibited List since 2014 on the basis of comparable evidence. Whether ranolazine, a mechanistically distinct late sodium current inhibitor, produces analogous performance-modifying effects in the absence of myocardial ischemia has not been systematically examined. This exploratory, hypothesis-generating study characterized the functional exercise and structural echocardiographic correlates of chronic ranolazine and trimetazidine administration in healthy rats.
Methods: Twenty-four male Sprague–Dawley rats were randomized in a blinded, parallel-group design to ranolazine (50 mg/kg/day), trimetazidine (10 mg/kg/day), or saline control (n = 8 per group) for 30 days. Two control-group rats died under ketamine-xylazine anesthesia during baseline (day 0) echocardiography, before any study data were collected, and were excluded from all subsequent analyses, yielding a final analytic sample of 22 rats (control, n = 6; trimetazidine, n = 8; ranolazine, n = 8). Forced swimming, rotarod testing, and transthoracic echocardiography were performed at baseline, day 15, and day 30. Because Shapiro–Wilk testing indicated non-normal distributions, non-parametric statistics (Kruskal–Wallis, Friedman, Wilcoxon signed-rank with Bonferroni-adjusted post-hoc thresholds) were applied a priori, and exact p-values are reported throughout.
Results: Total swimming time differed significantly between groups (ranolazine 39,668 s [33,794–43,838]; trimetazidine 35,694 s [30,776–39,516]; control 32,426 s [29,389–34,453]; p = 0.006), with ranolazine exceeding trimetazidine in sessions 16–18 (p < 0.001). Rotarod performance was unchanged across groups and time (p > 0.05 for all comparisons). Echocardiography showed small but statistically significant increases in interventricular septal thickness and calculated left ventricular mass in all three groups, including controls, with ejection fraction and fractional shortening preserved throughout.
Conclusions: Chronic ranolazine administration was associated with exercise-performance changes that paralleled, and in later sessions exceeded, those produced by trimetazidine, together with modest echocardiographic changes that are compatible with, but not proof of, physiological cardiac remodeling. Because the present design did not include biochemical, histological, electrocardiographic, or direct oxygen-consumption confirmation, and because the structural changes occurred in controls as well as treated animals, these observations should be regarded as hypothesis-generating rather than mechanistically conclusive. They identify ranolazine as a candidate worthy of further, more deeply mechanistic investigation rather than establishing, on their own, a basis for anti-doping action.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12872-026-06339-x.
Related
- Effects of Pulmonary Vein Isolation on Left Atrial Hemodynamic and Mechanical Function: Insights from Advanced and Emerging Echocardiographic Parameters in Responders and Non-Responders
- Echocardiographic Parameters in the Assessment of Tricuspid Regurgitation Prognosis: What Is New?
- Coffee Consumption, Serum Copeptin, and Selected Echocardiographic Parameters in Patients with ADPKD: A Cross-Sectional Study
- Association of Exercise-Induced Pulmonary Hypertension and Echocardiographic Parameters of Cardiac Function: A Systematic Review and Meta-Analysis
- Prognostic Value of Conventional Echocardiographic Parameters of Right Ventricular Dysfunction in a Real-World Cohort of Patients With Acute Pulmonary Embolism.
BibTeX
@article{kılıc2026beyond,
title = {{Beyond angina: Ranolazine is associated with increased forced-swimming endurance and altered echocardiographic parameters in healthy rats: a comparative study with Trimetazidine}},
author = {Şahhan Kılıç and Akın Torun and Süha Asal and Cumaali Demirtaş and Serkan Dilmen and Tufan Çınar and Ahmet Lütfullah Orhan and Mehmet Uzun},
journal = {BMC Cardiovascular Disorders},
year = {2026},
month = jul,
doi = {10.1186/s12872-026-06339-x},
url = {https://doi.org/10.1186/s12872-026-06339-x},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Beyond angina: Ranolazine is associated with increased forced-swimming endurance and altered echocardiographic parameters in healthy rats: a comparative study with Trimetazidine
AU - Şahhan Kılıç
AU - Akın Torun
AU - Süha Asal
AU - Cumaali Demirtaş
AU - Serkan Dilmen
AU - Tufan Çınar
AU - Ahmet Lütfullah Orhan
AU - Mehmet Uzun
PY - 2026
DA - 2026/07/29
JO - BMC Cardiovascular Disorders
DO - 10.1186/s12872-026-06339-x
UR - https://doi.org/10.1186/s12872-026-06339-x
AB - Background: Anti-anginal agents that modulate myocardial substrate metabolism, such as ranolazine and trimetazidine, are pharmacologically capable of altering exercise performance independently of their licensed indication in ischemic heart disease. Trimetazidine has been included on the World Anti-Doping Agency (WADA) Prohibited List since 2014 on the basis of comparable evidence. Whether ranolazine, a mechanistically distinct late sodium current inhibitor, produces analogous performance-modifying effects in the absence of myocardial ischemia has not been systematically examined. This exploratory, hypothesis-generating study characterized the functional exercise and structural echocardiographic correlates of chronic ranolazine and trimetazidine administration in healthy rats. Methods: Twenty-four male Sprague–Dawley rats were randomized in a blinded, parallel-group design to ranolazine (50 mg/kg/day), trimetazidine (10 mg/kg/day), or saline control (n = 8 per group) for 30 days. Two control-group rats died under ketamine-xylazine anesthesia during baseline (day 0) echocardiography, before any study data were collected, and were excluded from all subsequent analyses, yielding a final analytic sample of 22 rats (control, n = 6; trimetazidine, n = 8; ranolazine, n = 8). Forced swimming, rotarod testing, and transthoracic echocardiography were performed at baseline, day 15, and day 30. Because Shapiro–Wilk testing indicated non-normal distributions, non-parametric statistics (Kruskal–Wallis, Friedman, Wilcoxon signed-rank with Bonferroni-adjusted post-hoc thresholds) were applied a priori, and exact p-values are reported throughout. Results: Total swimming time differed significantly between groups (ranolazine 39,668 s [33,794–43,838]; trimetazidine 35,694 s [30,776–39,516]; control 32,426 s [29,389–34,453]; p = 0.006), with ranolazine exceeding trimetazidine in sessions 16–18 (p < 0.001). Rotarod performance was unchanged across groups and time (p > 0.05 for all comparisons). Echocardiography showed small but statistically significant increases in interventricular septal thickness and calculated left ventricular mass in all three groups, including controls, with ejection fraction and fractional shortening preserved throughout. Conclusions: Chronic ranolazine administration was associated with exercise-performance changes that paralleled, and in later sessions exceeded, those produced by trimetazidine, together with modest echocardiographic changes that are compatible with, but not proof of, physiological cardiac remodeling. Because the present design did not include biochemical, histological, electrocardiographic, or direct oxygen-consumption confirmation, and because the structural changes occurred in controls as well as treated animals, these observations should be regarded as hypothesis-generating rather than mechanistically conclusive. They identify ranolazine as a candidate worthy of further, more deeply mechanistic investigation rather than establishing, on their own, a basis for anti-doping action. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12872-026-06339-x.
SN - 1471-2261
ER -