Τίτλος:
The beneficial effects of ranolazine on cardiac function after myocardial infarction are greater in diabetic than in nondiabetic rats
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Ranolazine (RAN) is known to exert both anti-ischemic and antidiabetic actions. Thus, this study has explored the hypothesis that RAN would have greater effect on the recovery of cardiac function in diabetic mellitus (DM) rat hearts following myocardial infarction (MI). Myocardial infarction was induced in nondiabetic (MI, n= 14) and diabetic (streptozotocin induced; DM-MI, n= 13)Wistar rats by permanent ligation of the left coronary artery. Cardiac function was evaluated using echocardiography (left ventricular ejection fraction %) and in isolated heart preparations by measuring left ventricular developed pressure (LVDP), and the positive and negative first derivative of LVDP (+dp/dt). Ranolazine (20 mg/kg, ip once a day) was administered 24 hours after surgical procedure for 4 weeks to nondiabetic (MIRAN, n=17) and diabetic rats (DM-MIRAN, n=15). The RANimproved the recovery of function in both the nondiabetic and the diabetic postinfarcted hearts but this effect was greater and achieved statistical significance only in the diabetic group. The RAN resulted in increased levels of phosphorylated protein kinase B (Akt) and mammalian target of rapamycin (mTOR, a component of Akt signaling) in both nondiabetic and diabetic infarcted heartswithout changes in the activation of mitogen-activated protein kinases (MAPKs; p38MAPK, c-JunN-terminal kinase, and extracellular signal-regulated kinase). In addition, in diabetic hearts, RANresulted in a significant increase in the ratio of sarcoplasmic Ca2-ATPase/phospholamban (a target of Akt signaling, 2.0-fold increase) and increased levels of phosphorylated calcium-regulated adenosine monophosphate-activated protein kinase (AMPK; 2.0-fold increase). In diabetic animals, RANincreased insulin and lowered glucose levels in serum. In conclusion, the beneficial effect of RANon the recovery of cardiac function afterMIwas greater inDMrats. This response was associatedwith activation of Akt/mTOR and AMPK.These findings provide a plausible explanation for the results of the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial,which showed a greater antianginal effect of RAN in patients with coronary artery disease and diabetes.
Συγγραφείς:
Mourouzis, I.
Mantzouratou, P.
Galanopoulos, G.
Kostakou, E.
Dhalla, A.K.
Belardinelli, L.
Pantos, C.
Περιοδικό:
Journal of Cardiovascular Pharmacology and Therapeutics
Εκδότης:
SAGE Publications Ltd
Λέξεις-κλειδιά:
glucose; insulin; mammalian target of rapamycin; mitogen activated protein kinase; mitogen activated protein kinase 14; protein kinase B; ranolazine; streptozocin; stress activated protein kinase; acetanilide derivative; enzyme inhibitor; glucose blood level; insulin; mitogen activated protein kinase p38; piperazine derivative; protein kinase B; ranolazine, animal experiment; animal model; animal tissue; Article; controlled study; coronary artery ligation; drug effect; echocardiography; glucose blood level; heart ejection fraction; heart function; heart infarction; heart left ventricle pressure; insulin blood level; isolated heart; male; non insulin dependent diabetes mellitus; nonhuman; priority journal; rat; sarcoplasmic reticulum; streptozotocin-induced diabetes mellitus; Wistar rat; animal; blood; comparative study; complication; disease model; drug effects; experimental diabetes mellitus; heart function test; heart left ventricle function; metabolism; Myocardial Infarction; pathophysiology; polyacrylamide gel electrophoresis; treatment outcome, Acetanilides; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Echocardiography; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Heart Function Tests; Insulin; Male; Myocardial Infarction; p38 Mitogen-Activated Protein Kinases; Piperazines; Proto-Oncogene Proteins c-akt; Ranolazine; Rats; Rats, Wistar; Treatment Outcome; Ventricular Function, Left
DOI:
10.1177/1074248414524481
