The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts

Abstract

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague-Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs-Henseleit solution containing 11 mmol/L glucose, 100 muU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output x heart rate (in (mL/min).(beats/min).10-2), was deteriorated in diabetic (73 +/- 4) and TMZ-treated diabetic (61 +/- 7) groups compared with control (119 +/- 3) and TMZ-treated controls (131 +/- 6). TMZ treatment increased coronary flow in TMZ-treated control (23 +/- 1 mL/min) hearts compared with untreated controls (18 +/- 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 mumol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.

Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy

“…In fact, diabetes mellitus doubles the likelihood of having a heart attack (Donnelly et al, 2000). Alterations in cardiac mitochondrial energy metabolism are believed to contribute to the development of diabetic cardiomyopathies (How et al, 2007;Onay-Besikci et al, 2007;Sharma et al, 2008;Rijzewijk et al, 2009). For instance, hearts from animals or humans with diabetes mellitus or obesity are characterized by elevated fatty acid oxidation rates (Lopaschuk and Tsang, 1987;Mazumder et al, 2004;Peterson et al, 2004;Carley and Severson, 2005;Herrero et al, 2006).…”

“…These alterations in cardiac energy metabolism precede the development of glucose intolerance and cardiac hypertrophy (Buchanan et al, 2005). While the role of energy metabolism is likely to be much more complex, it is becoming clear that excessively high fatty acid oxidation rates contribute to the abnormalities in energy metabolism and cardiac function observed in diabetic cardiomyopathy (How et al, 2007;Onay-Besikci et al, 2007;Sharma et al, 2008).…”

Trimetazidine Revisited: A Comprehensive Review of the Pharmacological Effects and Analytical Techniques for the Determination of Trimetazidine

“…When applied to isolated coronary artery and mesenteric vein strips, TMZ induced dose‐dependent relaxations in prostaglandin F2‐precontracted vessels (Toda et al 1982). We also observed an increase in coronary flow rate in rats chronically treated with TMZ (Onay‐Besikci et al 2007).…”

“…We have not been able to show a reduction in glycemia of diabetic rats with chronic TMZ treatment. However, we reported that the mRNA levels of 3‐KAT, the mitochondrial enzyme inhibited by TMZ, were higher in diabetic rat hearts when compared to control rat hearts (Onay‐Besikci et al 2007). Coronary flow rates were also higher in nondiabetic rat hearts treated with TMZ (Onay‐Besikci et al 2007)…”

Trimetazidina como aditivo em solução cardioplégica sem pré-tratamento não traz proteção adicional ao miocárdio isquêmico: estudo em modelo suíno de coração isolado

“…Studies in rats prove the benefit of the pretreatment effect with trimetazidine in isolated working heart models [34][35][36]. Studies in patients pretreated with pre-trimetazidine undergone CABG show benefit in several parameters.…”