Beyond angina: Ranolazine is associated with increased forced-swimming endurance and altered echocardiographic...

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.

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.

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.

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.