Dichloroacetate (DCA), a stimulant of pyruvic dehydrogenase (PDH) has been shown to ameliorate lactic acidosis and improve cardiac performance in human shock. Previously we have shown that DCA improves myocardial performance when hearts removed from endotoxin shocked rats (LD 50-6 hrs) are perfused in the working configuration. Stroke work increases 61%, the activity of PDH rose over two-fold, and ATP content of the hearts returned to control levels by the treatment. Subsequently, we have also shown that the effects of DCA are additive with ouabain and amrinone in this model. We propose to determine the basis of this inotropic action of DCA. Using the isolated working perfused heart and calcium tolerant isolated cardiac myocytes from four complimentary models of heart failure, (Acute, high dose endotoxin, chronic low dose endotoxin, in vitro ischemia, and in vitro anoxia). The following questions will be addressed: A) Is the effect of DCA dependent upon the presence of glucose in the perfusate or do other carbohydrates permit the expression of the DCA effect? B) Is DCA effective in situations in which the myocardial dysfunctions is not accompanied by a diminution of ATP stores? C) Does DCA return the entire myocardial high energy phosphate profile to normal? D) Does DCA change the diastolic compliance of the metabolically stressed myocardium? E) Does DCA treatment change the cytosolic levels of free calcium in myocytes from metabolically stressed hearts? From this data we will correlate the improvement in mechanical function with myocardial levels of A) high energy phosphates, B) lactate C) pyruvate dehydrogenase activation and D) rates of substrate oxidation. The results of these studies should elucidate the basis of the inotrophic effect of DCA and suggest new methods to support the metabolically stressed myocardium.
| Burns, A H; Burns, L A; Jurenka, L U et al. (1991) Myocardial metabolic effects of in vivo hydralazine treatment of streptozotocin-diabetic rats. Am J Physiol 260:H516-21 |
| Racey-Burns, L A; Burns, A H; Summer, W R et al. (1989) The effect of dichloroacetate on the isolated no flow arrested rat heart. Life Sci 44:2015-23 |
