Streptozotocin directly impairs cardiac contractile function in isolated ventricular myocytes via a p38 map kinase-dependent oxidative stress mechanism.
Streptozotocin (STZ) has long been used to induce experimental diabetes mellitus to study diabetic complications such as diabetic cardiomyopathy. However, direct impact of STZ on cardiac function is unknown. This study was designed to evaluate the cardiac contractile effect of STZ in isolated adult rat ventricular myocytes. Contractile properties were assessed with an IonOptix MyoCam system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca2+ handling was evaluated with the fluorescent dye fura-2. Acute exposure of STZ (10(-9)-10(-5) M) depressed PS, prolonged TR90, and decreased electrically stimulated intracellular Ca2+ rise in a concentration-dependent manner. TPS,+/-dL/dt, resting intracellular Ca2+ level, and intracellular Ca2+ clearing rate were unaffected. The STZ-induced mechanical alterations were alleviated by the antioxidant vitamin C (100 microM) and the p38 MAP kinase inhibitor SB203580 (1 microM). 2', 7'-Dichlorofluorescein diacetate staining revealed enhanced production of reactive oxygen species following STZ treatment, which was prevented by either vitamin C or SB203580. Collectively, our data provided convincing evidence that the tool drug for experimental diabetes STZ may itself cause deleterious cardiac contractile dysfunction via an oxidative stress and p38 MAP kinase-dependent mechanism. Thus, caution should be taken when assessing diabetic heart complications using STZ-induced diabetic models.
Wold
Loren E
LE
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
Ren
Jun
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013311:Streptozocin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D001205:Ascorbic Acid; D002118:Calcium