Des Rosiers. Fatty acid oxidation and its impact on response of spontaneously hypertensive rat hearts to an adrenergic stress: benefits of a medium-chain fatty acid. Am J Physiol Heart Circ Physiol 288: H1425-H1436, 2005. First published November 18, 2004; doi:10.1152/ajpheart.00722.2004.-The spontaneously hypertensive rat (SHR) is a model of cardiomyopathy characterized by a restricted use of exogenous long-chain fatty acid (LCFA) for energy production. The aims of the present study were to document the functional and metabolic response of the SHR heart under conditions of increased energy demand and the effects of a medium-chain fatty acid (MCFA; octanoate) supplementation in this situation. Hearts were perfused ex vivo in a working mode with physiological concentrations of substrates and hormones and subjected to an adrenergic stimulation (epinephrine, 10 M).13 C-labeled substrates were used to assess substrate selection for energy production. Compared with control Wistar rat hearts, SHR hearts showed an impaired response to the adrenergic stimulation as reflected by 1) a smaller increase in contractility and developed pressure, 2) a faster decline in the aortic flow, and 3) greater cardiac tissue damage (lactate dehydrogenase release: 1,577 Ϯ 118 vs. 825 Ϯ 44 mU/min, P Ͻ 0.01). At the metabolic level, SHR hearts presented 1) a reduced exogenous LCFA contribution to the citric acid cycle flux (16 Ϯ 1 vs. 44 Ϯ 4%, P Ͻ 0.001) and an enhanced contribution of endogenous substrates (20 Ϯ 4 vs. 1 Ϯ 4%, P Ͻ 0.01); and 2) an increased lactate production from glycolysis, with a greater lactate-to-pyruvate production ratio. Addition of 0.2 mM octanoate reduced lactate dehydrogenase release (1,145 Ϯ 155 vs. 1,890 Ϯ 89 mU/min, P Ͻ 0.001) and increased exogenous fatty acid contribution to energy metabolism (23.7 Ϯ 1.3 vs. 15.8 Ϯ 0.8%, P Ͻ 0.01), which was accompanied by an equivalent decrease in unlabeled endogenous substrate contribution, possibly triglycerides (11.6 Ϯ 1.5 vs. 19.0 Ϯ 1.2%, P Ͻ 0.01). Taken altogether, these results demonstrate that the SHR heart shows an impaired capacity to withstand an acute adrenergic stress, which can be improved by increasing the contribution of exogenous fatty acid oxidation to energy production by MCFA supplementation. isolated working rat heart perfusion; citric acid cycle;13 C mass isotopomer analysis; fatty acid translocase/CD36; epinephrine ACCUMULATING EVIDENCE INDICATES that alterations in substrate selection for energy production can affect the heart's susceptibility to injury as well as the development of hypertrophy and heart failure (2,8,19,47,57). Specifically, interventions favoring carbohydrate over fatty acid (FA) oxidation were repeatedly shown to enhance the function of the ischemicreperfused heart (27, 51) or the failing heart (51). This notion has led to the development of new drugs, such as ranolazine, oxfenicine, and trimetazidine, whose effects are attributed to inhibition of FA oxidation (47, 51). What remains to be clarified, however, is how much can FA oxid...