AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 297: H1411-H1420, 2009. First published July 24, 2009; doi:10.1152/ajpheart.01269.2008
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Dimethylthiourea normalizes velocity-dependent, but not force-dependent, index of ventricular performance in diabetic rats: role of myosin heavy chain isozyme

Dong-Feng Yeih,1 Hung-I Yeh,2 Ho-Tsung Hsin,1 Lian-Yu Lin,3 Fu-Tien Chiang,3 Chuen-Den Tseng,3 Shu-Hsun Chu,1 and Yung-Zu Tseng3

1Department of Cardiology, Far Eastern Memorial Hospital, Pan-Chiao, Taipei County; 2Departments of Internal Medicine and Medical Research, Mackay Memorial Hospital; Mackay Medical College; Taipei Medical University, Taipei; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Submitted December 8, 2008 ; accepted in final form July 13, 2009

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 Qmax (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.

myocyte enhancer factor-2; transcription factor; contractile function; oxidative stress; antioxidant


Address for reprint requests and other correspondence: Y.-Z. Tseng, Dept. of Internal Medicine, National Taiwan Univ. Hospital, 7, Chung-Shan South Rd., Taipei, 10016 Taiwan, Republic of China (e-mail: yztseng{at}ntu.edu.tw).






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