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Restoration of Cardiomyocyte Functional Properties by Angiotensin II Receptor Blockade in Diabetic Rats

¹ Department of Preclinical and Clinical Pharmacology, Center of Molecular Medicine, University of Florence, Florence, Italy
² Section of Metabolic Diseases, Endocrine Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy

Recent evidence suggests that blockade of the renin-angiotensin system ameliorates diabetes-induced cardiac dysfunction, but the mechanisms involved in this process remain elusive. We investigated the effect of treatment with an angiotensin II receptor blocker, losartan, on the metabolic and electrophysiological properties of cardiomyocytes isolated from streptozotocin-induced diabetic (STZ) rats. Glucose uptake and electrophysiological properties were measured in ventricular cardiomyocytes from normoglycemic and STZ-induced diabetic rats given vehicle or 20 mg · kg^–1 · day^–1 losartan for 8 weeks. Insulin and ß-adrenergic stimulation failed to increase the glucose uptake rate in STZ cardiomyocytes, whereas the -adrenergic effect persisted. Concurrently, a typical prolongation of action potential duration (APD) and a decrease of transient outward current (I_to) were recorded in patch-clamped STZ myocytes. Treatment with losartan did not affect body weight or glycemia of diabetic or control animals. However, in losartan-treated STZ-induced diabetic rats, ß-adrenergic–mediated enhancement of glucose uptake was completely recovered. APD and I_to were similar to those measured in losartan-treated control rats. A significant (P < 0.0001) correlation between metabolic and electrophysiological parameters was found in control, diabetic, and losartan-treated diabetic rats. Thus, angiotensin receptor blockade protects the heart from the development of cellular alterations typically associated with diabetes. These data suggest that angiotensin receptor blockers may represent a new therapeutic strategy for diabetic cardiomyopathy.

Key Words: ANG II, angiotensin II • AP, action potential • APD, action potential duration • ARB, angiotensin receptor blocker • AT₁, type 1 angiotensin II receptor • 2-DG, 2-deoxy-D-glucose • HP, holding potential • I_to, transient outward current • STZ, streptozotocin

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