title: Chronic treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase, attenuates ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive diabetic animals.
abstract: Diabetes is associated with increased incidence of cardiovascular disease. Mechanisms that contribute to development of diabetic cardiopathy are not well understood. Phosphatidylinositol 3-kinase (PI3K) is a family of protein kinases that play an important role in regulation of cardiac function. It has been shown that inhibition of certain PI3K enzymes may produce cardiovascular protection. The aim of the present study was to determine whether chronic treatment with LY294002, an inhibitor of PI3K, can attenuate diabetes-induced cardiac dysfunction in isolated hearts obtained from normotensive and hypertensive rats. Recovery of cardiac function after 40 min of global ischemia and 30 min of reperfusion, measured as left ventricular developed pressure, left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance, was worse in hearts obtained from diabetic and/or hypertensive animals compared to their respective controls. Treatment with LY294002 (1.2 mg/kg/day) for 4 weeks significantly prevented diabetes-induced cardiac dysfunction in both normotensive and hypertensive rats. Treatment with LY294002 did not significantly alter blood pressure or blood glucose levels. These results suggest that inhibition of PI3K signaling pathways can prevent ischemia/reperfusion-induced cardiac dysfunction in normotensive and hypertensive rats without correcting hyperglycemia or high blood pressure.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait. ibenter@hsc.edu.kw
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Rashdan
authors.forename: Jasbir S
authors.initials: JS
authors.lastname: Juggi
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.forename: Saghir
authors.initials: S
authors.lastname: Akhtar
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002867:Chromones / Q000008:administration & dosage*; D003331:Coronary Vessels / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012039:Regional Blood Flow; D015398:Signal Transduction; D014655:Vascular Resistance / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one