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Title: Combined Inhibition of Angiotensin Converting Enzyme and NADPH Oxidase Prevents Diabetes-Induced Cardiac
Authors: Amal Sanat Al-Sumairi 
Supervisor: Prof. Ibrahim F. Benter
Keywords: Angiotensin;NADPH Oxidase;Diabetes-Induced Cardiac;Diabetes Mellitus
Issue Date: 2012
Publisher:  Kuwait university - college of graduate studies
Abstract: Diabetes Mellitus is a metabolic disease responsible for a wide spectrum of pathological alterations which negatively impact human life. Among all complications from diabetes, cardiovascular disease continues to be the primary cause of morbidity and mortality. Although diabetics are at a much higher incidence for coronary artery disease and high blood pressure, diabetic cardiomyopathy may develop independent of any macroand micro-vascular diseases leading to compromised myocardial structure and function. Ventricular hypertrophy, fibrosis, diastolic and systolic dysfunction often develop as a result of diabetes. Many pathophysiological mechanisms have been postulated for the onset and progression of diabetic cardiac dysfunction, including growth factors, cytokines, activation of the rennin-angiotensin system (RAS), and oxidative stress. Angiotensinconverting enzyme-1 inhibitors (ACEIs), such as ramipril, provide the most effective clinical intervention to date. These inhibitors provide a cardioprotective effects through the inhibition of angiotensin II formation. Oxidative stress, via increased production of reactive oxygen species (ROS), has also been implicated in the cardiac dysfunction. The enzyme, NADPH oxidase which is a potent cytosolic generator of ROS, is composed of two membrane-associated components, p22 phox and gp91 phox, and four major cytosolic components, p47 phox, p40 phox, p67 phox and rac-1/2. Upregulation of NADPH oxidase has been demonstrated in diabetes. Apocynin, a NADPH oxidase inhibitor, has been shown to improve renal function in experimental models of diabetic nephropathy. The RAS has also involved in the production of ROS via direct and indirect effects of angiotensin II via NADPH. This study aimed to test whether the combination of ramipril and apocynin would v provide greater cardioprotection than each drug alone. The study was carried out on isolated hearts from streptozotocin-induced diabetic male Wistar rats representing type 1 diabetes clinically observed in humans. Our results showed that treatment with apocynin resulted generally in improved cardiac recovery in non-diabetic control and diabetic hearts. Treatment with ramipril improved cardiac recovery in both non-diabetic control and diabetic hearts. Addition of apocynin to ramipril treatment resulted in improved recovery compared to ramipril alone in control hearts only in LVEDP, -dp/dt, and CF. However, combination treatment generally resulted in better recovery than each drug alone in all cardiac parameters in diabetic hearts. In general, administration of apocynin during perfusion produced better cardiac recovery than during reperfusion and the opposite was true for ramipril. Taken together, the obtained results indicate that the combination of NADPH oxidase blockade with ACE inhibition is a promising regimen which warrants further investigation as a way to confer additional cardioprotection against ischemiareperfusion injury in diabetes.
Appears in Programs:0550 Pharmacology (M.Sc.)

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