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Hemorrhagic coagulopathy is involved in the morbidity and mortality of trauma patients. Nonetheless, many aspects of the mechanisms underlying this disorder are poorly understood. We have therefore investigated changes in fibrinogen metabolism and coagulation function after a moderate hemorrhagic shock, using a new stable isotope approach. Twelve pigs were randomly divided into the control (C) and hemorrhage (H) groups. Hemorrhage was induced by bleeding 35% total blood volume over a 30-min period. A primed constant infusion of [1-[sup.13]C]phenylalanine (Phe), [d.sub.5]-phenylalanine, and [alpha]-[1-[sup.13]C]ketoisocaproate (KIC) was given to quantify fibrinogen synthesis and breakdown, together with measurements of circulating liver enzyme activities and coagulation function. Mean arterial pressure was decreased by hemorrhage from 89 [+ or -] 4 mmHg in C to 47 [+ or -] 4 mmHg in H (P < 0.05), followed by a rebound to 68 [+ or -] 5 mmHg afterward. Fibrinogen fractional synthesis rate increased from 2.7 [+ or -] 0.2%/h in C to 4.2 [+ or -] 0.4%/h in H by Phe (P < 0.05) and from 3.1 [+ or -] 0.4%/h in C to 4.4 [+ or -] 0.5%/h in H by KIC (P < 0.05). Fibrinogen fractional breakdown rate increased from 3.6 _+ 1.0%/h in C to 12.9 [+ or -] 1.8%/h in H (P < 0.05). The absolute breakdown rate accelerated from 3.0 [+ or -] 0.4 mg x [kg.sup.-1] x [h.sup.-1] in C to 5.4 [+ or -] 0.6 mg x [kg.sup.-1] x [h.sup.-1] in H (P < 0.05), but the absolute synthesis rate remained unchanged. These metabolic changes were accompanied by a reduction in blood clotting time to 92.7 [+ or -] 1.6% of the baseline value by hemorrhage (P < 0.05). No changes were found in liver enzyme activities. We conclude that the observed changes in coagulation after hemorrhagic shock are mechanistically related to the acute acceleration of fibrinogen degradation. stable isotopes; fibrinogen metabolism; hemorrhage; coagulation

Moderate severity heart failure does not involve a down-regulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 287: H1538-H1543. 2004. First published June 10, 2004; 10.1152/ajpheart.00281.2004.--Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of tree fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,[10-.sup.3]H]oteate, [[U-.sup.14]C]glucose, and [[1-.sup.13]C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity tot malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomemon. cardiac: metabolism; malonyl CoA

Normal cardiac metabolism requires continuous replenishment (anaplerosis) of catalytic intermediates of the citric acid cycle. Little is known about the quantitative aspects of propionate as a substrate of in vivo anaplerosis; therefore, we measured the rate of propionate entry into the citric acid cycle in hearts of anesthetized pigs. [U-[sup.13][C.sub.3]]propionate (0.25 mM) was infused in a coronary artery branch for I h via an extracorporeal perfusion circuit, and cardiac biopsies were analyzed for the mass isotopomer distribution of citric acid cycle intermediates. Infusion of propionate did not affect myocardial oxygen consumption, heart rate, or contractile function. In the infused territory, propionate infusion did not affect uptake of glucose and lactate but decreased free fatty acid uptake by one-half (P < 0.05). Propionate extraction and uptake were 57.4 [+ or -] 3.3% and 0.078 [+ or -] 0.009 [micro]mol * [min.sup.-1] * [g.sup.-1]. Anaplerosis from propionate, calculated from the mass isotopomer distribution of succinate, accounted for 8.9 [+ or -] 1.3% of the citric acid cycle flux. Propioylcarnitine release accounted for only 0.033 [+ or -] 0.002% of propionate uptake. Methylcitrate did not accumulate. Thus administration of a low concentration of propionate appears to be a convenient and safe way to boost anaplerosis in the heart. tricarboxylic acid cycle; cataplerosis; mass isotopomer analysis; mass spectrometry

The role of plasma free fatty acids and de novo synthesized fatty acids in the synthesis of lung surfactant phosphatidylcholine (PC) has been studied. A new stable isotope tracer model was used in infusing (1,2-13C2)acetate and uniformly labeled (U-13C16)palmitate in nine overnight fasted pigs. Surfactant kinetics were measured during the basal state and during low-dose glucose infusion. Results indicate glucose does not affect PC synthesis. Plasma is also the main contributor of fatty acids for surfactant PC synthesis.

Martini, Wenjun Z., Oivind Irtun, David L. Chinkes, Robert E. Barrow, and Robert R. Wolfe. Glucose effects on lung surfactant kinetics in conscious pigs. Am J Physiol Endocrinol Metab 279: E920-E926, 2000.--The primary goal of this study was to investigate the effects of glucose infusion on surfactant phosphatidylcholine (PC) metabolic kinetics in the lungs. A new stable isotope tracer model was used in which [1,2-[sup.13][C.sub.2]]acetate and uniformly labeled [U-[sup.13][C.sub.16]]palmitate were infused in 12 normal overnight-fasted pigs to quantify lung surfactant kinetics with or without glucose infusion (24 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]). With glucose infusion, the rate of surfactant PC incorporation from de novo synthesized palmitate increased from the control value of 2.1 [+ or -] 0.2 to 15.5 [+ or -] 1.9 nmol PC-bound palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05), whereas the incorporation rate from plasma preformed palmitate decreased from the control value of 20.9 [+ or -] 1.9 to 11.6 [+ or -] 1.1 nmol palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05). The palmitate composition in lamellar body surfactant PC increased from the control value of 61.7 [+ or -] 2.1% to 75.9 [+ or -] 0.6% (P [is less than] 0.05). The surfactant PC secretion rate decreased from the control value of 239.0 [+ or -] 26.1 to 81.9 [+ or -] 5.3 nmol PC-bound palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05). We conclude that, whereas surfactant secretion was inhibited by glucose infusion, neither total surfactant PC synthesis nor the surfactant PC pool size was significantly affected due to an increased reliance on de novo synthesized fatty acids. phosphatidylcholine; isotope; synthesis; secretion