Effects of fumarate on cardiorenal injury markers in normotensive Wistar rats

Abstract

Fumarate, the tricarboxylic acid cycle metabolite, which evokes an antihypertensive action has been reported to exert paradoxical actions that worsen hypertension-induced organ damage. This study investigates any link between these paradoxical effects and applied doses of fumarate. Male and female Wistar rats (150-180 g) were grouped into three (3) groups containing eight (8) animals each. Group I received distilled water (3 ml/kg, po), and groups II-IV received fumarate (50, 150, and 500 mg/kg, po) respectively for 28 days. Urine was collected for 24 hours via metabolic cages on days 0 and 28. After 28 days, animals were sacrificed, and blood was collected via cardiac puncture for biochemical analyses. Fumarate exerted a dose-dependent increase in the serum levels of troponin, CK-MB, and myoglobin (p<0.001) in both male and female rats. Urine volumes were significantly reduced and peaked in rats of both sexes at 500 mg/kg of fumarate. This was followed by a simultaneous increase in sodium excretion in male rats (50.3 ± 9.3 vs 74.7 ± 4.2 mmol/L, p<0.05) at 150 mg/kg and female rats (43.3 ± 1.6 vs 89.0 ± 0.6 mmol/L, p<0.001) at 150 mg/kg. Proteinuria was only significantly elevated at 500 mg/kg in fumarate-treated male rats (92.3 ± 3.1 vs 151.5 ± 15.6 mg/24 h, p<0.05). In female rats, urinary protein excretion was increased at all doses (p<0.05). The results from this study showed that the paradoxical increase in myocardial injury is dose-dependent and occurs on sustained administration.