Right ventricular pressure overload alters cardiac lipid composition.

INTRODUCTION: Right ventricular (RV) failure due to pressure load is an important determinant of clinical outcome in pulmonary hypertension, congenital heart disease and left ventricular failure. The last decades it has become clear that metabolic dysregulation is associated with the development of RV-failure. However, underlying mechanisms remain to be unraveled. Recently, disruption of intracardiac lipid content has been suggested as potential inducer of RV failure. In the present study, we used a rat model of RV-dysfunction and aimed to obtain insight in temporal changes in RV-function, -remodelling and -metabolism and relate this to RV lipid content. METHODS AND RESULTS: Male Wistar WU rats were subjected to pulmonary artery banding (n = 25) or sham surgery (n = 14) and cellular, hemodynamic and metabolic assessments took place after 2, 5 and 12 weeks. In this model RV dysfunction and remodelling occurred, including early upregulation of oxidative stress markers. After 12 weeks of pressure load, lipidomics revealed significant decreases of myocardial diglycerides and cardiolipins, driven by (poly-)unsaturated forms. The decrease of cardiolipins was driven by its most abundant form, tetralinoleoylcardiolipin. Mitochondrial capacity for fatty acid oxidation preserved, while the capacity for glucose oxidation increased. CONCLUSION: RV dysfunction due to pressure load, is associated with decreased intracardiac unsaturated lipids, especially tetralinoleoylcardiolipin. This was accompanied with preserved mitochondrial capacity regarding fatty acids oxidation, with increased capacity for glucose oxidation, and early activation of oxidative stress. We suggest that early interventions should be directed towards preservation of lipid availability as possible mean in order to prevent RV failure.

Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet.

AIM: Inhibition of the acetyl-CoA carboxylase (ACC) system, consisting of the isozymes ACC1 and ACC2, may be beneficial for treatment of insulin resistance and/or obesity by interfering with de novo lipogenesis and beta-oxidation. We have evaluated effects of pharmacological inhibition of ACC by soraphen (SP) on high fat (HF) diet-induced insulin resistance in mice. METHOD: Male C57Bl6/J mice were fed control chow, a HF diet or a HF diet supplemented with SP (50 or 100 mg/kg/day). RESULTS: Body weight gain and total body fat content of SP-treated animals were significantly reduced compared with HF-fed mice. Fractional synthesis of palmitate was significantly reduced in mice treated with SP, indicative for ACC1 inhibition. Plasma beta-hydroxybutyrate levels were significantly elevated by SP, reflecting simultaneous inhibition of ACC2 activity. Mice treated with SP showed improved peripheral insulin sensitivity, as assessed by hyperinsulinaemic euglycaemic clamps. CONCLUSION: Pharmacological inhibition of the ACC system is of potential use for treatment of key components of the metabolic syndrome.

[Deficiency of the fatty-acid oxidising enzyme medium-chain acyl-CoA dehydrogenase (MCAD) in an adult, detected during a neonatal screening programme]. / Defïciëntie van het vetzuuroxidatie-enzym middenketen-acyl-coënzym-A-dehydrogenase (MCAD) bij een volwassene, opgespoord tijdens een proefproject voor neonatale screening]

In a trial running since October 2003 in the Dutch provinces of Friesland, Groningen, Drenthe and Overijssel neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency has been added to the regular newborn screening programme for phenylketonuria, congenital hypothyroidism and adrenogenital syndrome. One of the questions to be answered by this trial is the cause of the strong variation in clinical expression of the disorder. Underdiagnosing is an important factor in this phenomenon, as shown by the data of a family of which the case histories of the two oldest children were discussed in this journal in 1965. Both children died at a very young age. Recently, MCAD deficiency was diagnosed in the youngest child of this family, now a 34-year-old woman. This family history illustrates the variable clinical expression of MCAD deficiency, which can cause death but can also run a milder or even subclinical course. Moreover, this family history shows that the underdiagnosis of MCAD deficiency in deceased children may be a cause of the apparently limited clinical detection rate of this disease, for which a simple treatment consisting of life-style and dietary measures is available after diagnosis.

Metabolic responses to moderate exercise in lambs with aortopulmonary shunts.

In a previous study we found, after an overnight fast of 18 hours, a lower arterial glucose concentration and a depressed glycogenolysis in lambs with aortopulmonary left-to-right shunts. During exercise, glucose and free fatty acids (FFA) concentrations normally increase. The aim of this study was to investigate whether the shunt lambs could compensate for a depressed glycogenolysis by increasing gluconeogenesis and by increasing levels of blood substrates such as FFA and glycerol during exercise. Therefore, we investigated glucose kinetics, with [U-(13)C]glucose, in five 7-week-old shunt and 7 control lambs of a similar age, at rest and during moderate exercise (treadmill; 50% of VO(2) peak). The glucose production rate and the rate of disappearance of glucose were lower in shunt than in control lambs, both at rest and during exercise. We found no difference in metabolic clearance rate of glucose, glucose recycling, or gluconeogenesis between both groups of lambs. Glycogenolysis was at rest lower in shunt than in control lambs and tended to be lower during exercise. The arterial concentrations of pyruvate, lactate, FFA, and total and free glycerol increased during exercise in both groups of lambs. In conclusion, shunt lambs have lower arterial glucose concentrations than control lambs, both at rest and during moderate exercise. This was due to a lower glucose production rate, in particular a lower glycogenolysis. In addition, the reduced glycogenolysis rate was not offset by an increase in gluconeogenesis nor by an increase in other substrates that can be utilized by working muscles.

Effects of exercise and isoproterenol on hemodynamics and myocardial VO2 in lambs with aortopulmonary shunts.

To compare hemodynamic changes induced by isoproterenol and exercise stress tests in individuals with and without left ventricular volume load, we studied 10 lambs with an aortopulmonary shunt [58 +/- 4% (SE) of left ventricular output] 2 wk after the shunt was created. Two studies, isoproterenol infusion at 0.1 microgram.kg-1.min-1 and treadmill exercise at 76 +/- 4% of predetermined maximal O2 consumption (VO2) were performed in each lamb in random order on different days. Identical experiments were performed in nine lambs without shunts. Isoproterenol and exercise induced similar changes in heart rate (43 +/- 5%); systemic (72 +/- 7%), pulmonary (35 +/- 3%), and shunt blood flows (8 +/- 6%); and stroke volume (NS) in shunt lambs. Aortic systolic pressure increased less during isoproterenol infusion than during exercise (7 +/- 3 vs. 27 +/- 5%), and left atrial pressure decreased during isoproterenol infusion (-23 +/- 4%) but changed in an opposite direction during exercise (7 +/- 6%). These changes were accompanied by a smaller increase in myocardial VO2 during isoproterenol infusion than during exercise (5.0 +/- 0.7 to 5.3 +/- 0.6 and 5.3 +/- 0.8 to 7.3 +/- 0.9 mumol.beat-1 x 100 g-1, respectively). In control lambs, stroke volume decreased during isoproterenol infusion despite an equal decrease in left atrial pressure as in shunt lambs. In conclusion, isoproterenol better stimulates the blood flow changes during exercise in shunt than in control lambs probably because of their higher ventricular filling pressures. In interpreting isoproterenol stress tests it should, however, be kept in mind that these changes are realized at a lower work load for the heart.

Left ventricular oxygen and substrate uptake in chronically hypoxemic lambs.

Myocardial oxygen demand may be increased in chronically hypoxemic lambs because of their increased heart rate. Therefore, we determined whether left ventricular (LV) oxygen supply, oxygen uptake and oxygen demand were proportionally increased in 6-wk-old lambs, after 4 wk of hypoxemia (n = 15), as compared with control lambs (n = 14). In addition, we determined whether LV glucose, pyruvate, lactate, FFA and ketoacids uptake were altered in hypoxemic lambs, because of alterations in arterial glucose, pyruvate and lactate concentrations, that may occur in hypoxemia. Hypoxemia was induced by the combination of an atrial septal defect and pulmonary stenosis. Arterial oxygen saturation was decreased in hypoxemic lambs (67 +/- 8 versus 91 +/- 3%, p < 0.001), Hb concentration was increased, so that arterial oxygen concentration was similar in both groups of lambs. Myocardial mass (61 +/- 13 versus 44 +/- 9 g, p < 0.001) and total myocardial blood flow (117 +/- 36 versus 62 +/- 27 mL.min-1, p < 0.001) were increased, mainly due to right ventricular hypertrophy. LV oxygen demand, estimated by the rate pressure product (2072 +/- 465 versus 1467 +/- 358 kPa.beat.min-1, p < 0.001), and oxygen uptake (723 +/- 223 versus 556 +/- 184 mumol.min-1 x 100 g-1, p < 0.05) were proportionally increased in hypoxemic lambs. LV oxygen supply increased linearly with oxygen uptake (r = 0.96) in all lambs, by adjustments in LV blood flow, which was increased in hypoxemic lambs (168 +/- 41 versus 134 +/- 45 mL.min-1 x 100g-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial substrate uptake in lambs with and without aortopulmonary shunts during strenuous exercise.

Increased myocardial fatty acid uptake during acute exercise could adversely affect myocardial O2 consumption in lambs with left-to-right shunts, which would be unfavorable in view of their decreased coronary blood flow reserve. Therefore, we studied myocardial substrate uptake (glucose, lactate, pyruvate, free fatty acids, triglycerides, beta-hydroxybutyrate, and acetoacetate) in 10 7-wk-old lambs with an aortopulmonary left-to-right shunt [61 +/- 3% (SE) of left ventricular output] and 9 control lambs during strenuous treadmill exercise. The hemodynamic reaction to exercise was similar in shunt and control lambs. The peripheral metabolic response to exercise was also similar in the two groups: glucose free fatty acids, and, most prominently, lactate concentrations increased. Myocardial O2 consumption increased but less in shunt than in control lambs because of a smaller increase in heart rate. In both groups myocardial lactate uptake increased substantially at the cost of other substrates, providing the heart with 40% of its oxidative metabolism. Fatty acid uptake was not different between the two groups. In conclusion, our data reveal no essential differences in myocardial substrate uptake between shunt and control lambs during a substantial circulatory load.

Mechanism of biliary lipid secretion in the rat: a role for bile acid-independent bile flow?

Bile acid-induced lipid secretion was compared in unanesthetized normal control and Groningen Yellow Wistar rats during variations in endogenous bile acid output. Groningen Yellow rats express a genetic defect in the biliary secretion of various organic anions. During a 5-hr period after interruption of the enterohepatic circulation, bile acid secretion decreased from 36.4 +/- 1.8 to 1.9 +/- 0.3 mumol per 30 min in normal control rats and from 37.1 +/- 2.8 to 1.8 +/- 0.2 mumol per 30 min in Groningen Yellow rats, respectively (mean +/- S.E.M., n = 5). The relationship between bile acid secretion and bile flow showed similar slopes (normal control, 8.74 +/- 0.44 microliter/mumol and Groningen Yellow rats, 7.71 +/- 0.42 microliter/mumol) but different y-intercepts (normal control, 243 +/- 8 and Groningen Yellow, 127 +/- 4 microliters per 30 min; p < 0.001), corresponding to a 47% reduction of the bile acid-independent fraction of bile flow in Groningen Yellow rats. During the course of the experiment, the ratio of lipids (phospholipids plus cholesterol) to bile acids increased in both strains more than threefold but was permanently higher in Groningen Yellow than in normal control rats (p = 0.035), implying that Groningen Yellow rats continuously secreted more lipid per bile acid. No differences in bile acid pool composition or in bile canalicular membrane composition and fluidity between the two strains were detected. The results indicate that apart from previously demonstrated factors (bile acid concentration, bile acid composition and hydrophilic organic anion concentration in bile), another parameter affects the efficacy of bile acids to induce biliary lipid secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial blood flow and VO2 in lambs with an aortopulmonary shunt during strenuous exercise.

To determine how much myocardial O2 consumption (VO2) would increase during an additional load on the heart in shunt as compared with control lambs, we studied 12 7-wk-old lambs with an aortopulmonary left-to-right shunt (59 +/- 3% of left ventricular output, mean +/- SE) and 11 control lambs during exercise at 80% of their predetermined peak VO2 (VO2peak), at 12 +/- 1 days after surgery. During exercise, systolic aortic pressure increased by 25% in the two groups. Left atrial pressure and left ventricular stroke volume did not change significantly and remained considerably higher in shunt than in control lambs. Heart rate, however, increased less in shunt than in control lambs (163 +/- 8 to 235 +/- 8 vs. 107 +/- 7 to 230 +/- 8 beats/min). The same was true for left ventricular myocardial blood flow (245 +/- 19 to 391 +/- 27 vs. 128 +/- 10 to 320 +/- 45 ml.min-1 x 100 g-1) and myocardial VO2 (847 +/- 101 to 1,692 +/- 136 vs. 528 +/- 58 to 1,579 +/- 178 mumol O2 x min-1 x 100 g-1). We conclude that, despite the volume load, myocardial VO2 of shunt lambs does not increase to a greater extent than in control lambs during a considerable additional load on the heart.

Body fluid compartment volumes in chronically hypoxemic lambs.

Chronic hypoxemia is associated with a decreased growth rate and a decreased rate of cell division. In lambs with experimental cyanotic heart disease, the gain in body mass was decreased. In this study, we determined to what extent the lower body mass in these lambs was related to alterations in body fluid compartment volumes, specifically whether intracellular volume was decreased. Therefore, fluid compartment volumes were studied in nine lambs, after 3 to 4 wk of experimental cyanotic heart disease, and in 13 control lambs. Hypoxemic lambs had a lower arterial oxygen saturation (65 +/- 11 versus 91 +/- 2%, p < 0.001) and a higher Hb concentration (142 +/- 16 versus 101 +/- 8 g.L-1, p < 0.001). The lower body mass in hypoxemic lambs (10.5 +/- 2.3 versus 13.0 +/- 2.8 kg) could be mainly accounted for by a decrease in intracellular water volume (4.7 +/- 1.3 versus 6.6 +/- 1.5 L, p < 0.01). Total body water (753 +/- 27 versus 780 +/- 40 mL.kg-1) and extracellular water volume (307 +/- 25 versus 277 +/- 15 mL.kg-1) in hypoxemic lambs were not significantly different from those in control lambs, but intracellular water volume was decreased (445 +/- 27 versus 501 +/- 35 mL.kg-1, p < 0.01). The ratio of extracellular to intracellular water volume was higher in hypoxemic lambs (0.69 +/- 0.10 versus 0.55 +/- 0.04, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of bile acid-induced biliary lipid secretion in the rat: effect of conjugated bilirubin.

We have compared the effects of bilirubin and bilirubin ditaurate (BDT) on biliary phospholipid and cholesterol secretion in unanesthetized normal Wistar (NW) and Groningen Yellow (GY) Wistar rats under various experimental conditions. GY rats express a genetic defect in biliary secretion, but not in hepatic uptake, of various organic anions. Under physiological conditions, NW and GY rats showed similar biliary secretion rates of bile acids and of bilirubin, despite the fact that bilirubin concentrations in GY plasma were 25 times as high and in GY livers three times as high as in NW plasma and livers, respectively. Secretion of cholesterol and phospholipids was not impaired in GY rats under these conditions. Biliary secretion of intravenously injected BDT (3 mumol/100 g body wt) was delayed in eight-day bile-diverted GY rats and showed lower peak values when compared with NW rats. The inhibitory effects of BDT on phospholipid and cholesterol secretion paralleled these differences, being delayed and much less pronounced in GY rats. No overshoot in phospholipid or cholesterol secretion was observed when bilirubin output returned to preinjection values. Stimulation of [14C]choline-labeled phospholipid secretion after a bolus injection of taurochenodeoxycholic acid (1 mumol/100 g body wt) closely followed biliary bile acid concentration. Similarly, inhibition of labeled phospholipid secretion by BDT closely paralleled the biliary bilirubin concentration. Gel filtration studies (Sepharose 4B-CL) under micelle-preserving conditions demonstrated a specific interaction of BDT with biliary bile acids. The presented data indicate that conjugated bilirubin does not inhibit biliary lipid secretion via interaction with bile acids inside the hepatocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood volume and body fluid compartments in lambs with aortopulmonary left-to-right shunts.

A left-to-right shunt is accompanied by an increased plasma and blood volume. Since this is likely realized through renin/aldosterone-mediated salt and water retention, other body fluid compartments may be changed too. Therefore, we studied blood volume and body fluid compartments by a single-injection, triple-indicator dilution technique in nine 8-wk-old lambs with an aortopulmonary left-to-right shunt (55 +/- 3% of left ventricular output; mean +/- SEM) and in 11 control lambs, 2.5 wk after surgery. Systemic blood flow was maintained at the same level as in control lambs, but the aortic pressure of the shunt lambs was lower. Blood volume in shunt lambs was larger than in control lambs (110 +/- 6 vs. 84 +/- 7 ml/kg, P < 0.001) through an increase in plasma volume, which correlated significantly with the magnitude of the left-to-right shunt (r = 0.81, P < 0.01). Red blood cell volume was equal to that of control lambs. Evidence was obtained that the increase in plasma volume was induced by a transient increase in renin (8.0 +/- 2.2 vs. 1.6 +/- 0.2 nmol.l-1.h-1; P < 0.02) and aldosterone (0.51 +/- 0.14 vs. 0.24 +/- 0.09 nmol/liter) concentrations. Interstitial water volume, however, was not significantly different from that in control lambs. The amount of intravascular protein was significantly higher than in control lambs (5.0 +/- 0.3 vs. 3.5 +/- 0.2 g/kg body mass, P < 0.001). There were no significant differences in intracellular and total body water volumes between the two groups. We conclude that the increased amount of intravascular protein confines the fluid retained by the kidneys to the vascular compartment.

Myocardial carbohydrate, ketone, and fatty acid uptake in conscious lambs with aortopulmonary shunts.

A left to right shunt increases myocardial work and is often accompanied by increased catecholamine levels. Because both increased myocardial work and increased catecholamine levels may induce increased fatty acid utilization, which could increase resting myocardial oxygen consumption and therefore unfavorably affect coronary reserve, we studied myocardial uptake of glucose, pyruvate, lactate, beta-OH-butyrate, acetoacetate, FFA, and triglycerides in 12 7-wk-old lambs with aortopulmonary left to right shunts (58 +/- 2% of left ventricular output, mean +/- SEM) and in 10 control lambs 2 wk after surgery. Despite the shunt, systemic blood flow in the shunt lambs was maintained at the same level as in the control lambs. This was accomplished by an increased heart rate and stroke volume. Furthermore, the shunt was accompanied by an increased myocardial oxygen consumption in the shunt lambs (834 +/- 70 versus 528 +/- 43 mumol O2.min-1 x 100 g-1; p less than 0.05). There were no significant differences in arterial substrate concentrations between the two groups. The same was true for arteriovenous differences across the myocardium, with the exception of lactate, which was substantially higher in shunt than in control lambs (72 +/- 25 versus 18 +/- 23 mumol/L; p less than 0.05). As a consequence, myocardial lactate uptake in the shunt lambs was increased 15-fold (18 +/- 6 versus 1 +/- 2 mumol.min-1 x 100 g-1; p less than 0.02), whereas uptake of the other substrates merely paralleled the increased myocardial blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation and characterization of canalicular and basolateral plasma membrane fractions from human liver.

A method is described for the isolation of subfractions from human liver plasma membranes, enriched in canalicular domains (cLPM) and basolateral domains (blLPM), respectively, and the results are compared to those obtained with rat liver. The studies were performed in 18 human livers. The cLPM (isolated at densities 1.103-1.127 for human and 1.036-1.127 for rat cLPM) from human as well as rat liver showed a lower density than the blLPM (1.141-1.161 for human and 1.151-1.172 for rat blLPM). Human and rat blLPM were characterized by increased levels of (Na+/K+)-ATPase (relative enrichment 33 and 21, respectively). Both human and rat cLPM showed high specific activities of leucine aminopeptidase; relative enrichment factors were 42 and 31, respectively. Mg(2+)-ATPase and alkaline phosphatase, specific canalicular enzymes in rat liver, were only slightly enriched in the cLPM of human liver, which indicates that these enzymes are not suitable as marker enzymes for human liver cLPM. Both cLPM and blLPM of human and rat origin were only slightly contaminated with mitochondria, lysosomes, Golgi membranes and endoplasmic reticulum. Total recoveries of cLPM and blLPM were 0.02 mg protein/g liver each for the human membrane preparations, compared to 0.07 and 0.16 mg protein/g liver for the membranes prepared from rat liver. Analysis of membrane fluidity revealed that the human liver cLPM were more rigid than blLPM (mean difference in fluorescence polarization PDPH 0.024). They contained more cholesterol (0.43 vs. 0.30 mumol/mg protein) and phospholipids (0.54 vs. 0.39 mumol/mg protein, respectively), which was compatible to rat liver plasma membrane fractions. This study shows that besides similarities, there are several differences between human and rat liver plasma membrane fractions.

Differential hepatic processing and biliary secretion of head-group and acyl chains of liposomal phosphatidylcholines.

To investigate the contribution of plasma-derived phosphatidylcholine (PC) to bile PC, the hepatic processing and biliary secretion of liposome-associated PC was studied in rats. For this purpose, small unilamellar vesicles (SUV), containing trace amounts of [2-palmitoyl-9,10-3H]dipalmitoylphosphatidylcholine ([palmitoyl-3H]DPPC), [choline-14C]-dipalmitoylphosphatidylcholine ([choline-14C]DPPC), di[14C]palmitoylphosphatidylcholine ([14C]DPPC) or di[1-14C]-oleoylphosphatidylcholine ([14C]DOPC), were administered intravenously to unanaesthetized rats, equipped with permanent catheters in heart and bile duct. Biliary secretion of the 14C-head-group label of DPPC was very slow (0.3% of injected dose in 4 h), whereas the [3H]palmitoyl label was secreted at a much higher rate (16% in 4 h), but only after substantial catabolism of the acyl chain. To study the latter process in more detail, we compared hepatic metabolism and biliary secretion of [1-14C]acyl-labelled DPPC and DOPC. In rats with an 8-day bile drainage, degradation products of the oleoyl chain were utilized for synthesis of bile acids, which were subsequently secreted into the bile (2% in 6 h). A much smaller fraction (0.6% in 6 h) was secreted as PC and lyso-PC. When bile drainage was started immediately after SUV injection, i.e. a situation with a low hepatic bile acid synthesis rate and a high phospholipid secretion, the secretion of [14C]DOPC-derived radioactivity in the form of bile acids was decreased (0.2% in 6 h), and that as (lyso-)PC increased (1.5% in 6 h). Biliary secretion of DPPC palmitoyl chains in bile-diverted rats was much less than that of the oleoyl chains, and occurred predominantly as PC and lyso-PC (0.6%, compared with 0.4% as bile acids in 6 h). Breath analyses demonstrated that a considerable fraction of both acyl chains was oxidized to CO2 and expired: 25.1% of the administered label for oleoyl chains and 13.4% for palmitoyl chains respectively in a 4 h period. The results of this study indicate that liposomal PC is only minimally secreted into bile via a direct pathway; the bulk is extensively degraded in the liver. Resulting products are partly secreted into bile, as bile acid or as resynthesized PC. There appears to be a quantitative difference in the metabolism of oleoyl and palmitoyl acyl chains.

Effects of nitroprusside on myocardial blood flow and oxygen consumption in conscious lambs with an aortopulmonary left-to-right shunt.

We studied the effect of vasodilation on regional myocardial blood flow and oxygen consumption of the left ventricular free wall by infusing 10 micrograms/kg/min sodium nitroprusside into 7-week-old conscious lambs with and without aortopulmonary left-to-right shunts. Resting myocardial oxygen consumption in the 13 shunt lambs was significantly higher than in the nine control lambs (989 +/- 104 [+/- SEM] vs. 432 +/- 41 mumol/min/100 g left ventricle). This was achieved by a significantly higher left ventricular myocardial blood flow (294 +/- 33 vs. 143 +/- 16 ml/min/100 g left ventricle) because the arteriovenous oxygen concentration difference across the left ventricular free wall was similar in shunt and control lambs. Infusion of nitroprusside did not significantly change myocardial oxygen consumption and regional myocardial blood flows at 10 and 50 minutes after the onset of the infusion. This occurred despite a substantial drop in aortic and left atrial pressures and stroke volume, which decreases wall stress as well as external work of the left ventricle. Heart rate, however, increased significantly. We postulate that, during infusion of nitroprusside, the potential decrease in myocardial oxygen consumption due to a decrease in wall stress and external work of the left ventricle is neutralized by the consequences of the increased heart rate. In view of this and because of its hemodynamic effects, we do not consider sodium nitroprusside useful in the treatment of circulatory congestion in patients with left-to-right shunts, normal arterial pressures, and normal systemic blood flows.

Biliary lipid secretion in the rat. The uncoupling of biliary cholesterol and phospholipid secretion from bile acid secretion by sulfated glycolithocholic acid.

Glycolithocholic acid and its sulfated derivative are major metabolites of the secondary bile acid lithocholic acid in man. Both compounds are known to induce cholestasis in experimental animals. We compared the effects of these endogenous hepatotoxins on bile production and biliary lipid composition in rats with chronic biliary drainage. The compounds were administered enterally at relatively low rates (5-50% of the rats' endogenous bile acid secretion in these experiments) to simulate enterohepatic circulation. Both compounds were substantially secreted into bile (more than 90% of dose); sulfated glycolithocholic acid unchanged and glycolithocholic acid after hepatic hydroxylation predominantly in the form of glyco-beta-muricholic acid (cf. Kuipers et al. (1986) Am. J. Physiol. 251, G189-G194). Neither glycolithocholic acid nor its sulfated derivative affected the biliary excretion of endogenous bile acids or bile flow in these experiments. In spite of this, phospholipid and cholesterol secretion were significantly reduced by sulfated glycolithocholic acid but were not altered by glycolithocholic acid. Phospholipid and cholesterol secretion rapidly decreased to 25 and 50% of their initial values, respectively, at biliary output rates of sulfated glycolithocholic acid up to 2 mumol/h, and did not further decrease when this output was increased to 6 mumol/h. Small unilamellar liposomes consisting of cholesterol, [Me-14C]choline-labeled phosphatidylcholine, phosphatidylserine and [3H]cholesteryl oleate in a 5:4:1:0.1 molar ratio were employed to label intrahepatic lipid pools. Administration of sulfated glycolithocholic acid slightly reduced bile acid synthesis from [3H]cholesteryl oleate, but significantly reduced the biliary secretion of [14C]phospholipid. Glycolithocholic acid did not affect the hepatic processing of liposomal lipids. It is concluded that sulfated glycolithocholic acid at low doses causes the uncoupling of biliary lipid secretion from that of bile acids, which might represent in initiating event in sulfated glycolithocholic acid hepatotoxicity.

Haematological characteristics of a new membrane oxygenator: the Cobe CML.

The new Cobe CML membrane oxygenator is more compact than other membrane oxygenators and has a combined venous and cardiotomy suction reservoir. Its size makes it as easy to use as a bubble oxygenator. The studies reported here were designed to show whether the excellent haemocompatibility found with other types of membrane oxygenators had ben compromised by the changes introduced in the Cobe CML oxygenator. Platelet number and function (ADP induced aggregation) plasma betathromboglobulin concentration and plasma haemoglobulin concentration were studied in nine patients where the Cobe CML oxygenator had been used and these were compared with ten patients managed with a Shiley S-100 bubble oxygenator. We conclude that the constructional changes of the Cobe CML oxygenator do not affect the haemocompatibility of this type of membrane oxygenator and that it remains significantly better than the Shiley S-100 bubble oxygenator.

Myocardial blood flow and VO2 in conscious lambs with an aortopulmonary shunt.

We measured myocardial blood flow (QLVFW) and O2 consumption of the left ventricular free wall (VO2, LVFW) in 13 chronically instrumented, 7-wk-old lambs with an aortopulmonary left-to-right shunt (S) and in 10 control lambs without a shunt (C). The measured VO2, LVFW was compared with the calculated values obtained by two predictive indexes, the rate-pressure product (RPP) and the pressure-work index (PWI). Measured VO2, LVFW in S lambs was significantly higher than in C lambs [983 +/- 104 (SE) vs. 475 +/- 57 mumol X min-1 X 100 g LV-1, P less than 0.001]. This was achieved by the significantly higher QLVFW (294 +/- 33 vs. 145 +/- 15 ml X min-1 X 100 g LV-1, P less than 0.002), since the arteriovenous O2 difference across the left ventricular free wall was similar in both groups of lambs. Total coronary blood flow per unit body mass in S lambs was higher than in C lambs (14.1 +/- 1.5 vs. 5.6 +/- 0.6 ml X min-1 X kg-1, P less than 0.001), not only because of the increased VO2, LVFW per unit muscle mass, but also because of the increased total heart weight (102.4 +/- 6.4 vs. 81.2 +/- 4.9 g, P less than 0.02). Correct estimation of VO2, LVFW by means of the RPP and the PWI was only possible in C lambs. In S lambs the estimated values were significantly lower than the measured ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of dynamic exercise in children and adolescents with moderate-to-small ventricular septal defects.

We studied the hemodynamic effects of dynamic exercise during cardiac catheterization in 35 children and adolescents with small-to-moderate ventricular septal defects. Eighteen of them exercised at 25% and 50% of their maximum workload and 17 exercised at 60%. There was no significant difference between the two groups with respect to age and body mass, height, and surface area. The changes evoked by exercise showed the same pattern at the different workloads, although they were more marked at the higher than at the lower percentage of maximum workload. During exercise the pulmonary vascular resistance did not change, in contrast to the systemic vascular resistance, which decreased. The pulmonary and systemic blood flows both increased, while the left-to-right shunt flow did not change, which led to a decrease of the left-to-right shunt fraction. As the heart rate increased and the shunt flow did not change, the shunt volume per beat decreased during exercise. We conclude that in patients with small-to-moderate ventricular septal defects the hemodynamic effects of dynamic exercise are favorable because the normal rise in systemic blood flow occurs without a corresponding increase in left-to-right shunt flow. Consequently, children and adolescents with such defects should not be restricted in their dynamic exercise activities.