Inhibitory effects of the D(-)isomer of 3-hydroxybutyrate on cardiac non-esterified fatty acid uptake and oxygen demand induced by norepinephrine in the intact dog.
The effects of ketosis on the norepinephrine-induced high rates of cardiac uptake of non-esterified fatty acids (NEFA = free fatty acids = FFA) and oxygen consumption were studied in anesthetized intact dogs. After a control infusion of norepinephrine (500 ng/kg.min into the left ventricle), the D(-) isomer or natural form of 3-hydroxybutyrate was infused intravenously as the arginine salt at rates of 20 mumol/kg.min in group A (10 dogs) and 80 mumol/kg.min in group B (10 dogs) and a second norepinephrine infusion was superimposed on the ketone treatment. At the time the effects of the second catecholamine infusion were measured, the arterial 3-hydroxybutyrate concentration averaged 1.2 +/- 0.1 mM in group A and 8.3 +/- 0.4 mM in group B, and the cardiac uptake of the ketone amounted to 17.4 +/- 0.6 and 35.8 +/- 5.3 mumol/min.100 g, respectively. Relative to the control norepinephrine infusion, the arterial NEFA concentration was reduced to 88 +/- 4% in group A and to 62 +/- 8% in group B, but the cardiac uptake of NEFA was significantly more depressed, to 65 +/- 7% in group A and to 35 +/- 8% in group B. These changes were not observed in ten non-ketotic animals under repeated norepinephrine infusion. Thus, ketosis inhibited the norepinephrine-stimulated uptake of NEFA, presumably through (1) a lowered availability of NEFA from arterial blood, attributable to a reduction of extracardiac lipolysis, and (2) competition of 3-hydroxybutyrate with NEFA for metabolism by the myocardium in the face of still high arterial NEFA concentrations, 1.7 +/- 0.1 mM in group A and 1.1 +/- 0.2 mM in group B. In both groups, the lowering of the contribution of NEFA to cardiac metabolism was associated with a reduction of the estimated oxygen demand per beat (ratio of cardiac oxygen consumption/min to the pressure-rate product), while the pressure response to norepinephrine was not modified. There was no evidence for abnormal cardiac function.
D020155:3-Hydroxybutyric Acid; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006885:Hydroxybutyrates / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007662:Ketosis / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects
D005230:Fatty Acids, Nonesterified; D006885:Hydroxybutyrates; D007328:Insulin; D020155:3-Hydroxybutyric Acid; D009638:Norepinephrine