Arterial Free Fatty Acid Concentration Research Articles

Dipropionylcysteine Ethyl Ester Compensates for Loss of Citric Acid Cycle Intermediates During Post Ischemia Reperfusion in the Pig Heart

During reperfusion, following myocardial ischemia, uncompensated loss of citric acid cycle (CAC) intermediates may impair CAC flux and energy transduction. Propionate has an anaplerotic effect when converted to the CAC intermediate succinyl-CoA, and may improve contractile recovery during reperfusion. Antioxidant therapy with N-acetylcysteine decreases reperfusion injury. To synergize the antioxidant effects of cysteine with the anaplerotic effects of propionate, we synthesized a novel bi-functional compound, N,S-dipropionyl cysteine ethyl ester (DPNCE) and tested its anaplerotic and anti-oxidative capacity in anesthetized pigs. Ischemia was induced by a 70% reduction in left anterior descending coronary artery flow for one hour, followed by 1 h of reperfusion. After 30 min of ischemia and throughout reperfusion animals were treated with saline or intravenous DPNCE (1.5 mg x kg(-1) x min(-1), n = 8/group). Arterial concentrations and myocardial propionate, cysteine, free fatty acids, glucose and lactate uptakes, cardiac mechanical functions, myocardial content of CAC intermediates and oxidative stress were assessed. Ischemia resulted in reduction in myocardial tissue concentration of CAC intermediates. DPNCE treatment elevated arterial propionate and cysteine concentrations and myocardial propionate uptake, and increased myocardial concentrations of citrate, succinate, fumarate, and malate compared to saline treated animals. DPNCE treatment did not affect blood pressure or myocardial contractile function, but increased arterial free fatty acid concentration and myocardial fatty acid uptake. Arterial cysteine concentration was elevated by DPNCE, but there was negligible myocardial cysteine uptake, and no change in markers of oxidative stress. DPNCE elevated arterial cysteine and propionate, and increased myocardial concentration of CAC intermediates, but did not affect mechanical function or oxidative stress.

Role of Body Fat Distribution and the Metabolic Complications of Obesity

An upper body/visceral fat distribution in obesity is closely linked with metabolic complications, whereas increased lower body fat is independently predictive of reduced cardiovascular risk. The measured functions of different fat depots with regards to fatty acid storage and release in health and obesity were reviewed. The adverse effects of experimentally increasing free fatty acid (FFA) concentrations on liver, muscle, pancreatic beta-cell, and endothelial function were noted. The most dramatic abnormality in FFA metabolism is failure to suppress FFA concentrations/adipose tissue lipolysis normally in response to postprandial hyperinsulinemia. Upper body sc fat delivers the majority of FFA to the systemic circulation under postabsorptive and postprandial conditions. In upper body obesity, portal FFA concentrations resulting from both systemic and visceral adipose tissue lipolysis may be significantly greater than arterial FFA concentrations, exposing the liver to even greater amounts of FFA. Visceral fat also releases sufficient IL-6 to increase portal vein IL-6 concentrations, which can affect hepatic metabolism as well. Lower body, upper body sc, and visceral fat depots have unique characteristics with regards to fatty acid metabolism. Selective dysregulation of these depots probably plays an important role with the metabolic complications of obesity.

The PPAR-α activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs

Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-alpha activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-alpha activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg.kg(-1).day(-1) orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-alpha in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-alpha mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-alpha in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-alpha activator does not alter myocardial metabolic or contractile responses to I/R in pigs.

Hyperlipidemia with Hypoglycemia Reduces Myocardial Oxygen Utilization Efficiency but not Contractile Function During Coronary Hypoperfusion

This study was designed to determine changes in myocardial contractile function and fuel selection during moderate coronary hypoperfusion in the presence of elevated plasma free fatty acid (FFA) at normal and reduced blood glucose concentrations. Coronary perfusion pressure (CPP) was sequentially lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery (LAD) of anesthetized, open-chest dogs. Regional glucose uptake (GU), fatty acid uptake (FAU), percentage segment shortening (%SS), and oxygen consumption (MV O2) were determined with normal arterial plasma FFA concentrations (Group 1) or with elevated FFA concentrations (Groups 2 and 3). In Group 3, glucose in the coronary perfusate blood was reduced from 3.53±0.36 to 0.15±0.03 m M by hemodialysis. In Group 1, FAU fell by 85% as CPP was lowered to 60 mmHg and remained depressed as CPP was reduced further; GU did not fall significantly. Hyperlipidemia in Group 2 did not alter GU at any CPP, but maintained FAU at baseline levels until CPP was lowered to 40 mmHg. At 40 mmHg CPP, myocardial function and metabolic variables were similar in Groups 1 and 2. In Group 3 at 40 mmHg, FAU increased four-fold and MV O2doubled v Groups 1 and 2, and GU fell to zero. Despite these metabolic changes, %SS in Group 3 was unchanged relative to Group 2. Addition of glucose to the dialysate prevented the effects of dialysis on FAU, GU, and MV O2. Thus, preferential glucose oxidation sustains myocardial oxygen utilization efficiency [(heart rate × %SS × maximum left ventricular pressure)/MV O2] during hypoperfusion. Blocking preferential glucose oxidation by combined hyperlipidemia and hypoglycemia lowers oxygen utilization efficiency, but does not compromise myocardial contractile function.

Whole body and splanchnic metabolic, circulatory, and thermal effects of oral vs. intravenous fat administration.

Relatively few studies on the physiological effects of fat administration have been published. In the present study, whole body and splanchnic oxygen consumption, blood flow, blood temperature, glucose and insulin economy, and arterial and hepatic venous concentrations of hemoglobin, free fatty acids (FFA), and glycerol were measured by indirect calorimetry and catheterization technique in seven healthy men before and during 2.5 h after oral ingestion of 850 kJ of fat and in five healthy men before and during a 2.5-h intravenous (i.v.) infusion of 850 kJ of fat. Oral fat increased the splanchnic blood flow by 57 +/- 25%, reduced the plasma volume by 6 +/- 1%, reduced the arterial concentrations of FFA and glycerol by 33 +/- 7 and 50 +/- 16%, respectively, and increased arterial insulin concentration by 52 +/- 12% despite a simultaneous reduction in splanchnic insulin release, thus suggesting a reduction of the extrasplanchnic extraction of insulin. None of these effects occurred during intravenous fat infusion, and it is suggested that intestinal hormones might elicit these effects. Body heat content, unaffected after oral fat, increased by 67 +/- 20 kJ during intravenous fat infusion.

Myocardial metabolism during graded intraportal verapamil infusion in awake dogs.

Verapamil produces comparatively greater in vivo left ventricular (LV) depression than other calcium channel antagonists produce, possibly because of myocardial metabolic derangements in addition to L-channel antagonism. Therefore, we studied myocardial lipid and carbohydrate usage and the effect of insulin treatment during progressive verapamil toxicity. Verapamil was infused through the portal vein to simulate oral overdose. Eighteen mongrel dogs were instrumented to measure multiple hemodynamic and metabolic parameters. After 1-week recovery, dogs underwent control euglycemic insulin dose-response studies (n = 6) in the conscious state: at 1,000 mU/mm insulin infusion rate, myocardial glucose and lactate extraction increased seven- and threefold, respectively with no change in coronary artery blood flow or ventricular elasticity and end-systole (Ees). In 12 separate dogs, intraportal graded verapamil toxicity was induced in 3 h by increasing the infusion rate hourly: 0.04 -- 0.08 -- 0.1 mg/kg/mm. At the end of hour 3, myocardial extraction of free fatty acids decreased from 33 +/- 4 to 9 +/- 3% (mean +/- SEM, p < 0.05), without significant change in myocardial blood flow or arterial free fatty acid concentration. Verapamil toxicity increased arterial glucose from 3.5 +/- 0.16 to 6.1 +/- 1.1 mM; simultaneously, myocardial glucose extraction doubled, although endogenous insulin concentrations did not increase. Arterial lactate concentrations and net myocardial lactate uptake both increased (p < 0.05 vs basal blue). Ees decreased from 28 +/- 1 mm Hg/mm (basal) to 20 +/- 2 mm Hg/mm (end of hour 3, p <0.05). Animals were randomized into two treatment groups; either (a) insulin-glucose (1,000 mU/mm, n 6; arterial glucose was clamped +/- 10% with 50% dextrose), or (b) saline controls (n = 6) that received equivalent volume of saline. After 1-h insulin treatment, Ees increased to 34 + 3 mm Hg; in controls, Ees was 15 +/- 3 mm Hg/mm (p < 0.05). With insulin-glucose treatment, neither myocardial glucose nor lactate extraction increased significantly (p = 0.06 for lactate). Verapamil therefore inhibits myocardial fatty acid uptake and impedes insulin-stimulated myocardial glucose uptake; under these conditions, insulin-glucose treatment increases myocardial contractile function independent of increased sugar transport. These findings indicate that verapamil toxicity produces myocardial insulin resistance and, potentially, nutrient deprivation that may contribute to clinically relevant negative inotropy.

Inhibition of fatty acid metabolism alters myocardial high-energy phosphates in vivo

We previously observed that isoproterenol (ISO) stimulation of the in situ porcine right ventricle (RV) increases the ratio of phosphocreatine (PCr) to ATP, accompanied by marked augmentation of myocardial free fatty acid (FFA) uptake. We hypothesized that increased FFA uptake and utilization cause the increase in PCr/ATP and that inhibition of FFA metabolism during ISO would prevent such an increase. In open-chest pigs, myocardial oxygen consumption (MVO2) of the RV free wall was increased with ISO (0.15 microgram.kg-1.min-1 iv) in the absence (n = 6) and presence (n = 6) of oxfenicine (65 mg/kg iv), an inhibitor of carnitine palmitoyltransferase I. ISO caused twofold increases in MVO2 and arterial FFA concentration. In the absence of oxfenicine, ISO increased RV FFA uptake from a control of 0.01 +/- 0.01 to 0.11 +/- 0.02 (SE) mumol.g-1.min-1. The PCr/ATP, measured by 31P-nuclear magnetic resonance spectroscopy, rose from 1.75 +/- 0.05 to 2.22 +/- 0.10 (P < 0.05). In the presence of oxfenicine, FFA uptake did not increase with ISO, despite elevated arterial FFA concentration. PCr/ATP fell from 1.65 +/- 0.05 to 1.53 +/- 0.07 (P < 0.01 vs. response without oxfenicine). In four additional pigs, arterial FFA concentration was increased in the absence of ISO by infusion of Intralipid and heparin sodium. PCr/ATP increased in each pig. When oxfenicine was administered with Intralipid, PCr/ATP decreased in each pig. We conclude that increased utilization of FFA raises the RV PCr/ATP ratio in vivo. Inhibition of FFA metabolism prevents the rise in PCr/ATP otherwise observed with ISO or with high arterial FFA.(ABSTRACT TRUNCATED AT 250 WORDS)

16 METABOLIC RESPONSE TO MODERATE EXERCISE IN LAMBS WITH AN AORTOPULMONARY SHUNT

The normal metabolic response to moderate exercise consists of a slight increase in glucose (glue) and a considerable increase in free fatty acids (FFA) in blood. In earlier studies we have demonstrated that at rest, after an overnight fast, lambs with an aortopulmonary shunt (SH) had lower concentrations of glue and FFA than control (C) lambs. We wondered, whether SH lambs with low glue and FFA were able to increase their arterial concentrations during exercise just like C lambs. Therefore, we studied 6 7-week-old SH lambs and 6 C lambs of the same age after an overnight fast at rest and during moderate exercise (tredmill; 50 % of Vo2-max; 30 rain). At rest as well as during exercise, 3 blood samples were taken at intervals of 10 min. At rest, mean arterial concentrations (mmol/l) of glue (SH: 3.37 ± 0.21 vs. C; 4.48 ± 0.53, mean ± SD, p < 0.05) and FFA (SH: 0.57 ± 0.17 vs. C: 0.80 ± 0.20, p < 0.05) were lower in SH than in C lambs. During exercise, glue (SH: 3.59 ± 0.19 vs. C: 5.15 ± 0.80, p < 0.05) and FFA (SH: 0.79 ± 0.32 vs. C: 1.23 ± 0.43, p < 0.05) increased significantly in SH and C lambs (p < 0.05). However, the relative increment of glue during exercise was lower in SH than in C lambs (7 ± 5 % vs. 15 ± 7 %, p < 0.05). The relative increment of FFA was not different (SH: 38 ± 37 % vs. C: 56 ± 47 %, p = 0.48). We conclude that, despite lower gluc and FFA at rest, SH lambs demonstrate a metabolic response of increment of gluc and FFA during moderate exercise like C lambs, However, the relative increment for gluc was lower in SH lambs. We speculate that this is due to an earlier glycogen depleted state in SH lambs.

Forearm ketone body metabolism in normal and in insulin-dependent diabetic patients

In insulin deficiency, there is excessive arterial delivery of free fatty acid (FFA) to muscles where they are converted to acetoacetyl-CoA and acetyl-CoA. These intermediates may be metabolized further to acetoacetate and beta-hydroxybutyrate, which can be released into the venous circulation. When ketone body (KB) tracers are infused in vivo, they are diluted across muscle tissue. This dilution may be due to 1) KB newly formed within muscle (ketogenesis); 2) exchange of tracer between labeled and unlabeled acetyl-CoA and acetoacetyl-CoA, intermediates common to the metabolism of both FFA and KB (pseudoketogenesis). Thus this study assessed whether such label exchange could be detected across the human forearm and whether an increased delivery of FFA in insulin-sufficient controls provoked dilution of labeled KB tracer comparable to that observed in insulin-deficient diabetics. Five normal and five insulin-dependent diabetic (IDDM) subjects were infused with labeled [3,4-13C2]-acetoacetate. [13C]KB enrichments were lower in forearm vein than in the artery, and dilution of labeled KB was always higher than that which could be explained by arterial-venous differences of unlabeled KB. When arterial FFA concentrations in normals were raised (Intralipid+heparin) to values comparable to those of the diabetics, no additional increase in forearm arteriovenous dilution of labeled KB was observed. Neither in the basal state nor under conditions of increased plasma FFA were we able to detect venous appearance of KB labeled in the first and in the second carbon atoms, a necessary consequence of pseudoketogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic hyperinsulinemia stimulates lactate extraction by heart muscle in the conscious dog

The effect of physiologic hyperinsulinemia on the net balance of lactate, glucose, and free fatty acids across the heart was studied in eight normal postabsorptive conscious dogs. After obtaining basal measurements of myocardial substrate balance, arterial plasma insulin was increased from 8 ± 1 to 68 ± 14 μU/mL while blood glucose was maintained constant (64 ± 1 mg/dL) using the hyperinsulinemic euglycemic clamp. Myocardial lactate uptake increased nearly fourfold, from 5.8 ± 1.8 to 22.4 ± 2.9 μmol/min ( P < .005). Despite a small increase in arterial lactate concentration from 0.46 ± 0.08 to 0.79 ± 0.11 mmol/L ( P < .02), the lactate extraction fraction increased from 23% ± 7% to 54% ± 2% ( P < .001) indicating an increased efficiency of lactate extraction. Euglycemic hyperinsulinemia led to a comparable increase in myocardial glucose uptake (6.7 ± 2.3 to 18.2 ± 3.7 μmol/min, P < .05). Arterial free fatty acid concentrations fell from 1.06 ± 0.13 to 0.35 ± 0.06 mmol/L ( P < .001) with a concomitant decline in the myocardial uptake of free fatty acids from 18.5 ± 5.3 to 5.8 ± 2.9 μmol/min ( P < .05). These results indicate that physiologic hyperinsulinemia increases lactate as well as glucose uptake in normal heart muscle.

Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance.

This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.

Excessive glucose administration in severe septic patients: A possible cause of fatty degeneration in skeletal muscle tissue

The ability to oxidise fatty acids was found to be impaired in severe septic patients with multiple organ failure. Thus, glucose still represents the major substrate for total parenteral nutrition in such conditions. To evaluate the effect of a high glucose load on peripheral substrate metabolism (priming dose: 10 g/5 min, constant infusion rate: 0.5g/kg·h) we studied muscle metabolism in five patients with hypodynamic septic shock (S) using the forearm technique. Data were compared to those of five patients 3 h after elective surgery (O), who were believed to show the typical metabolic pattern of a compensated stress response. Arterial and deep venous concentrations of glucose, lactate, pyruvate, acetoacetate (AcAc), β-hydroxbutyrate (β-HOB), free fatty acids (FFA), glycerol, oxygen, insulin, adrenalin and noradrenalin were determined in the basal period and during glucose infusion. Consistent with an impaired mobilisation of endogenous substrate stores basal arterial concentrations of FFA, β-HOB and AcAc were markedly lower in severe sepsis. In O glucose infusion resulted in a continuous increase of forearm glucose uptake, compensating falling rates of FFA and ketone body uptake due to decreased arterial supply. On the contrary, in S arterial supply of FFA, AcAc and β-HOB almost remained unchanged during glucose infusion. Nevertheless, muscular balances of FFA were affected significantly, changing from a basal release into uptake during glucose infusion (basal: −0.23 ± 0.17 μmol/100 g min; 10 min of glucose infusion: 0.30 ± 0.31; 20 min: 0.95 + 0.92 ∗; 40 min: 0.32 ± 0.26 ∗; ∗: p<0.05). This was related to a marked increase in muscular glucose uptake exceeding that of O significantly. Concomitant rates of muscular glycerol release stayed low indicating reduced hydrolytic rate of muscle triglycerides. Thus peripheral lipogenesis might arise from excessive glucose administration in such conditions due to an increased rate of muscular re-esterification of FFA. To avoid this adverse side effect administration of glucose calories should be limited to basal energy requirements.

Effects of glucose-insulin-potassium on intestinal hemodynamics and substrate utilization during endotoxemia.

This study examined the effects of endotoxin on small intestinal hemodynamics and metabolism with and without an infusion of glucose-insulin-potassium (GIK). Glucose uptake and lactate release were determined by arteriovenous differences across a segment of canine ileum, which was vascularly isolated in vivo, and by the direct measurement of intestinal blood flow. Free fatty acid (FFA) utilization by intestinal tissue was assessed by the constant infusion of albumin-bound [14C]palmitate and [3H]oleate. Endotoxemic dogs showed a sustained reduction of mean arterial blood pressure (MABP) and intestinal blood flow. In contrast, endotoxemic dogs infused with GIK demonstrated a decreased intestinal vascular resistance and an increased blood flow (two-fold), whereas MABP was transiently improved. Intestinal glucose uptake was not different from control values in endotoxemic animals; however, a sixfold increase was seen in shocked dogs treated with GIK. The endotoxin-induced increase in the plasma lactate concentration and intestinal lactate release was similar between dogs infused with saline or GIK. After endotoxin, the arterial FFA concentration remained unchanged and whole-body FFA turnover was decreased. FFA uptake by the gut was reduced, but FFA oxidation was not altered. Similar changes in FFA metabolism were seen in endotoxemic animals infused with GIK. The metabolic pattern after endotoxin suggests an elevated rate of aerobic glycolysis by the gut that increases the availability of lactate to the liver. Compared with saline-infused endotoxemic animals, GIK produced an elevation in glucose uptake without a further increase in lactate output, suggesting an increased storage of glucose by this tissue.

Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium

The effects on myocardial damage of metabolic interventions by nicotinic acid, oxfenicine, or a combination of the two were assessed in open-chest dogs exposed to coronary artery occlusion for 6 hours. The accumulation of metabolites of free fatty acids (FFAs) was studied in tissue samples of the left ventricle taken 60 minutes after coronary occlusion in separate animals. The percentage of the hypoperfused zone that evolved to infarction was 96 ± 3% (mean ± SEM) in control dogs, 74 ± 4% in dogs treated with nicotinic acid ( p < 0.05 vs control dogs), 72 ± 2% in dogs treated with oxfenicine ( p < 0.05 vs control dogs), and 54 ± 5% in dogs treated with combined nicotinic acid and oxfenicine ( p < 0.05 vs control dogs, p < 0.05 vs nicotinic acid and oxfenicine). Arterial FFA concentration was markedly reduced in dogs treated with nicotinic acid and those treated with combination nicotinic acid and oxfenicine. The accumulation of long-chain acyl carnitine was substantially reduced in the ischemic myocardium after nicotinic acid, oxfenicine, and a combination of the two, whereas the lowering of long-chain acyl CoA was less pronounced. Thus, nicotinic acid and oxfenicine, which depress myocardial FFA metabolism by different mechanisms, both reduce myocardial infarct size and their effects are additive.

Inhibition of fatty acid mobilization by arterial free fatty acid concentration.

Subcutaneous, inguinal adipose tissue from dogs was perfused with blood in which the free fatty acid (FFA) concentration was varied corresponding to FFA/albumin molar ratios between 1 and 6. Otherwise the composition of the perfusate was kept constant. In order to stimulate lipolysis, isoprenaline and theophyllamine were added to the perfusate. A raise in arterial FFA/albumin molar ratio was without influence on lipolysis (as reflected in the release of glycerol), but reduced the FFA release indicating an increased re-esterification. At FFA/albumin ratios above 3 a marked increase in vascular resistance was seen. This increase was partly reversible within the time of a perfusion. When lipolysis is stimulated in the intact organism, the effects of increasing arterial FFA/albumin ratio on re-esterification and vascular resistance may serve as feedback mechanisms regulating FFA mobilization.

Exchange of free fatty acids and glucose in leg tissues before and immediately after surgery

The present study was undertaken to investigate whether there is an augmented uptake of free fatty acids (FFA) in the leg tissues immediately after surgery when the energy expenditure of the leg is increased considerably. Eight patients were studied before and after cholecystectomy. Blood and plasma flow were determined in one leg, as well as arterio-venous concentration differences for oxygen, glycose, lactate and the total fraction of FFA. To determine uptake and release of FFA, 1-( 14C)-oleic acid was infused intravenously and the arterio-venous differences for ( 14C)-FFA were determined. The mean oxygen uptake in the leg increased from 0.72±0.06 mmol/min to 1.78±0.41 mmol/min. The uptake of free fatty acids in the leg did not increase significantly after cholecystectomy when compared to before operation in spite of the marked increase in oxygen uptake. Postoperatively there was, however, a positive linear relationship between the uptake of FFA and that of oxygen in the leg. The glucose uptake, after correction for released lactate, corresponded to 7% of the oxygen uptake before surgery and 13% after surgery. The arterial FFA concentration did not change. This study indicates that the combined possible contribution of glucose and free fatty acids to the oxidative energy metabolism of the leg tissues exceeded the oxygen uptake before, but not after surgery. In the postoperative state there was a positive correlation between oxygen uptake and FFA uptake in the leg.

Splanchnic and leg exchange of free fatty acids in patients with liver cirrhosis

Splanchnic and leg exchange of free fatty acids (FFA), glycerol and ketone bodies, as well as FFA turnover, were determined in the post-absorptive state in 8 patients with liver cirrhosis and in 6 healthy control subjects. The catheter technique was used together with tracer ([14C]oleate) infusion. The arterial concentrations of FFA, glycerol and ketone bodies were 2-6-fold higher in the patients than in the controls. The FFA turnover was 230% greater in the patients, while the fractional turnover was similar in the two groups. In the splanchnic region as well as in the leg, both FFA uptake and release were increased 2-4-fold in the patients. The fractional uptake of FFA was reduced in both areas, indicating that the augmented uptake was due to the high circulating FFA levels alone. The splanchnic production of ketone bodies was four times higher in the patients than in the controls (295 +/- 30 vs 87 +/- 11 mumol/min). The fraction of FFA converted to ketone bodies was greater (42 +/- 6 vs 20 +/- 5%, P less than 0.05), indicating that the accelerated ketone body production was a combined effect of raised FFA uptake and altered intrahepatic metabolism of FFA. The splanchnic production of glucose was reduced by approximately 50% in the patients, while the uptake of glycerol was augmented. The leg uptake of 3-hydroxybutyrate was increased 300% and the release of glycerol was 200% greater in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.

Starvation-Induced Ketone Body Production in the Conscious Unrestrained Miniature Pig

The effect of short-term starvation (up to 5 days) on hepatic ketone body production was investigated in the conscious unrestrained miniature pig in vivo. Starvation induced an increase in arterial free fatty acid concentration (0.2– 0.7mm) with a concomitant elevation in hepatic free fatty acid extraction [-1.4–5.7 µmol/kg · minute), r = 0.53, P < 0.005]. Ketone body production (sum of acetoacetate + β-hydroxybutyrate) increased from 1.5 to 5.8 µmol/(kg · minute) in parallel (r = 0.71, P < 0.0005). During starvation arterial insulin levels decreased, glucagon increased, cortisol remained unchanged and a “low T3 state” was observed. These data differ in some aspects from those reported for humans and dogs. Thus a species-specific variation in the fuel economy of the pig's body is proposed.starvation miniature pig hepatic ketogenesis hepatic free fatty acid extraction

Diet induced changes in sympatho-adrenal activity during submaximal exercise in relation to substrate utilization in man.

In order to study how the diet may influence sympatho-adrenal activity during exercise, 7 subjects were examined at rest and during submaximal exercise (25 min at 65% of VO2 max) on two occasions. The first occasion was preceded by 5 days on a carbohydrate poor diet (5% carbohydrate, 72% fat and 23% protein) and the second one by 5 days on a carbohydrate rich diet (78% carbohydrate, 8% fat and 14% protein) with the same energy content. Oxygen uptake, respiratory exchange ratio (R), heart rate and arterial plasma concentrations of adrenaline, noradrenaline, dopamine, insulin, glucose, lactate, free fatty acids (FFA), glycerol and beta-hydroxybutyrate were measured at rest and during exercise. Oxygen uptake and heart rate during exercise were higher and R was lower after the carbohydrate poor than after the carbohydrate rich diet. During exercise the arterial plasma concentrations of FFA, glycerol and beta-hydroxybutyrate were higher after the carbohydrate poor than after the carbohydrate rich diet whereas concentrations of insulin and lactate were lower. At rest arterial plasma noradrenaline and adrenaline levels were similar on the two diets (0.70 +/- 0.31 nM noradrenaline and 0.35 +/- 0.32 nM adrenaline one the carbohydrate rich diet, mean values +/- SD). Exercise induced increases in noradrenaline were more pronounced after the carbohydrate poor than after the carbohydrate rich diet (12.42 +/- 3.41 vs. 7.45 +/- 2.68 at 25 min of exercise, p less than 0.001). A similar, although more variable accentuation of exercise induced increases in adrenaline was found. It is concluded that, when compared to a carbohydrate rich diet, a carbohydrate poor diet increases the relative contribution of fat to oxidative metabolism and increases the sympatho-adrenal response to exercise. Stimulation of lipolysis by sympatho-adrenal mechanisms might be of importance for the substrate availability when carbohydrate intake in low.