Dimethylthiourea normalizes velocity-dependent, but not force-dependent, index of ventricular performance in diabetic rats: Role of myosin heavy chain isozyme
Journal
American Journal of Physiology - Heart and Circulatory Physiology
Journal Volume
297
Journal Issue
4
Pages
H1411-H1420
Date Issued
2009
Author(s)
Abstract
Hydroxyl radicals and hydrogen peroxide are involved in the pathogenesis of systolic dysfunction in diabetic rats, but the precise mechanisms and the effect of antioxidant therapy in diabetic subjects have not been elucidated. We aimed to evaluate the effects of dimethylthiourea (DMTU), a potent hydroxyl radical scavenger, on both force-dependent and velocity-dependent indexes of cardiac contractility in streptozotocin (STZ)-induced early and chronic diabetic rats. Seventy-two hours and 8 wk after STZ (55 mg/kg) injection, diabetic rats were randomized to either DMTU (50 mg·kg-1·day -1 ip) or vehicle treatment for 6 and 12 wk, respectively. All rats were then subjected to invasive hemodynamic studies. Maximal systolic elastance (Emax) and maximum theoretical flow (Qmax) were assessed by curve-fitting techniques in terms of the elastance-resistance model. Both normalized Emax (Emaxn) and afterload-adjusted Q max (Qmaxad) were depressed in diabetic rats, concomitant with altered myosin heavy chain (MHC) isoform composition and its upstream regulators, such as myocyte enhancer factor-2 (MEF-2) and heart autonomic nervous system and neural crest derivatives (HAND). In chronic diabetic rats, DMTU markedly attenuated the impairment in Qmaxad and normalized the expression of MEF-2 and eHAND and MHC isoform composition but exerted an insignificant benefit on Emaxn. Regarding preventive treatment, DMTU significantly ameliorated both Emaxn and Qmaxad in early diabetic rats. In conclusion, our study shows that DMTU has disparate effects on Qmaxad and Emaxn in chronic diabetic rats. The advantage of DMTU in chronic diabetic rats might involve normalization of MEF-2 and eHAND, as well as reversal of MHC isoform switch. Copyright ? 2009 the American Physiological Society.
SDGs
Other Subjects
dimethylthiourea; isoenzyme; myocyte enhancer factor 2; myosin heavy chain; animal experiment; article; controlled study; drug effect; drug mechanism; heart muscle contractility; hemodynamics; male; nonhuman; oxidative stress; priority journal; rat; streptozocin diabetes; Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Agents; Diabetes Mellitus, Experimental; Elasticity; Free Radical Scavengers; Hemodynamics; Hydroxyl Radical; Male; Myocardial Contraction; Myocardium; Myogenic Regulatory Factors; Myosin Heavy Chains; Oxidative Stress; Protein Isoforms; Rats; Rats, Wistar; Thiourea; Time Factors; Ventricular Dysfunction, Left
Type
journal article