title: 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.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Ankara University, Tandogan 06100, Ankara, Turkey. onay@pharmacy.ankara.edu.tr
authors.forename: Arzu
authors.initials: A
authors.lastname: Onay-Besikci
authors.forename: Sahika
authors.initials: S
authors.lastname: Guner
authors.forename: Ebru
authors.initials: E
authors.lastname: Arioglu
authors.forename: Isil
authors.initials: I
authors.lastname: Ozakca
authors.forename: A Tanju
authors.initials: AT
authors.lastname: Ozcelikay
authors.forename: V Melih
authors.initials: VM
authors.lastname: Altan
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015992:Body Mass Index; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004326:Drinking / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019308:Palmitic Acid / Q000378:metabolism; D010477:Perfusion / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin; D014292:Trimetazidine / Q000494:pharmacology*; D014325:Tromethamine / Q000008:administration & dosage; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; C074097:Krebs-Henseleit solution; D012333:RNA, Messenger; D014665:Vasodilator Agents; D014325:Tromethamine; D019308:Palmitic Acid; D013311:Streptozocin; D000102:Acetyl-CoA C-Acyltransferase; D005947:Glucose; D014292:Trimetazidine