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CARDIOVASCULAR

The Effect of NCX4016 [2-Acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl Ester] on the Consequences of Ischemia and Reperfusion in the Streptozotocin Diabetic Rat

Departments of Physiology and Pharmacology (S.G.B., B.L.F.) and Pharmaceutical Sciences (D.G.W.), Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom; School of Pharmacy, Robert Gordon University, Aberdeen, United Kingdom (C.L.W.); and William Harvey Research Institute, Barts and the London, Queen Mary School of Medicine and Dentistry, London, United Kingdom (I.V., T.W.)

The aim of this study was to assess the effect of chronic administration of NCX4016 [2 acetoxy-benzoate 2-(2-nitroxymethyl)-phenyl ester], a nitric oxide-releasing aspirin derivative on the consequences of coronary artery occlusion in streptozotocin-diabetic rats. Rats were made diabetic by injection of streptozotocin (60 mg kg^–1) and received insulin (2.5 U kg^–1 s.c.) daily for 4 weeks. Animals received vehicle (1 ml kg^–1 polyethylene glycol), aspirin (65.2 mg kg^–1), NCX4016 (60 mg kg^–1), or (iv) NCX4016 (120 mg kg^–1) orally, once daily for the last 5 days before coronary artery occlusion (CAO). One hour after the last dose, pentobarbital-anesthetized rats were subjected to CAO for 30 min followed by 120-min reperfusion. Neither drug significantly modified initial hemodynamics or plasma glucose levels compared with vehicle treatment in either nondiabetic or diabetic rats. Neither drug modified the total ventricular premature beat (VPB) count in normal animals, although NCX4016, but not aspirin, reduced the total VPB count and the incidence of ventricular tachycardia in diabetic rats. In nondiabetic animals, both aspirin and NCX4016 reduced infarct size. However, in diabetic rats, infarct size was reduced only by the larger dose of NCX4016 (120 mg kg^–1) but not by aspirin or the lower dose of NCX4016. These results demonstrate that the cardioprotective effects of NCX4016 are reduced in the presence of diabetes compared with the effects seen in nondiabetic animals. In summary, the present study confirms the protective effect of NCX4016 against ischemia-reperfusion injury in the normal rat heart and demonstrates for the first time its protective effect in the heart of streptozotocin-diabetic rats.

Address correspondence to: Dr. Brian Furman, Strathclyde University, Strathclyde Institute of Biomedical Sciences, John Arbuthnott Building, 27 Taylor Street, Glasgow G4 0NR, Scotland. E-mail: b.l.furman{at}strath.ac.uk

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