15N]glycine metabolism in normal and cirrhotic subjects

Following a single oral dose of 10 mg/kg of [15N]glycine, plasma [15N]glycine kinetics and urinary 15N excretion were measured in 12 cirrhosis patients and in 6 control subjects. Cirrhosis patients were divided into two groups of 6 patients with and without a history of hepatic encephalopathy designated as group II and group I, respectively. Thirty minutes after oral administration of labeled glycine, the plasma concentration of [15N]glycine was significantly higher in both cirrhosis groups than that in the control group (P less than 0.05 and P less than 0.01). The elimination constant of plasma [15N]glycine slightly decreased in group II, but not significantly. Urinary 15N excretion did not differ among the three groups, but the rate of urinary ammonia 15N in urinary 15N was significantly increased in group II (P less than 0.05). The whole-body protein flux did not differ among the three groups, but whole-body protein breakdown was significantly increased in group II cirrhosis patients (P less than 0.05). These findings indicated that the kinetics of glycine were substantially altered in severe cirrhosis patients. Because hepatic uptake and oxidation of glycine was well maintained even in group II, increased endogenous protein breakdown seemed to be responsible for hyperglycinemia and also for the negative nitrogen balance seen in this group.     

Wave-speed-determined flow limitation at peak flow in normal and asthmatic subjects

Pedersen, O. F., H. J. L. Brackel, J. M. Bogaard, and K. F. Kerrebijn. Wave-speed-determined flow limitation at peak flow innormal and asthmatic subjects. J. Appl.Physiol. 83(5): 1721-1732, 1997.The purpose ofthis study was to examine whether peak expiratory flow is determined bythe wave-speed flow-limiting mechanism. We examined 17 healthy subjectsand 11 subjects with stable asthma, the latter treated with inhaledbronchodilators and corticosteroids. We used an esophageal balloon anda Pitot-static probe positioned at five locations between the rightlower lobe and midtrachea to obtain dynamic area-transmural pressure(A-Ptm) curves as described (O. F. Pedersen, B. Thiessen, and S. Lyager. J. Appl.Physiol. 52: 357-369, 1982). From these curves weobtained cross-sectional area (A)and airway compliance (Caw = dA/dPtm) at PEF, calculated flow at wave speed {ws = A[A/(Caw*)^0.5],where  is density} and speed index is (SI = /ws). In 13 of 15 healthy andin 4 of 10 asthmatic subjects, who could produce satisfactory curves,SI at PEF was >0.9 at one or more measured positions. Alveolarpressure continued to increase after PEF was achieved, suggesting flowlimitation somewhere in the airway in all of these subjects. Weconclude that wave speed is reached in central airways at PEF in mostsubjects, but it cannot be excluded that wave speed is also reached inmore peripheral airways.

     

Influence of ethanol on the metabolism of perfused normal, fatty and cirrhotic rat livers

1. The influence of ethanol on the metabolism of perfused livers from normal rats and rats in various stages of development of dietary cirrhosis was studied. A choline-deficient, low-protein and high-fat diet was used. Results were obtained on oxygen consumption and carbon dioxide production, on glucose release and uptake by the liver and on changes in the concentrations of lactate and pyruvate and of β-hydroxybutyrate and acetoacetate in the perfusion medium. 2. Oxygen consumption and carbon dioxide production were lower in fatty and cirrhotic livers than in normal livers. Ethanol had no effect on the oxygen consumption of any of the various livers. After addition of ethanol to the perfusion medium carbon dioxide production ceased almost completely in normal livers. Only a slight decrease in the carbon dioxide production occurred in fatty and cirrhotic livers. 3. With every type of liver glucose was released from the liver into the perfusion medium during the initial control period. This release continued after the addition of ethanol to the perfusion medium in experiments with normal and fatty livers, whereas with cirrhotic livers a marked uptake of glucose from the medium was found. A simultaneous release of the glycolytic end products lactate and pyruvate into the medium occurred. 4. The production of ketone bodies was equal in normal and early fatty livers (6 weeks on the fat diet). It was smaller in late fatty livers (3–4 months on the fatty diet) and in cirrhotic livers. 5. The lactate/pyruvate concentration ratio in the perfusion medium increased from 11 to 67 with normal livers, from 12 to 16 with early fatty livers, from 13 to 26 with late fatty livers and from 21 to 55 with cirrhotic livers when the livers were perfused with a medium containing ethanol. The β-hydroxybutyrate/acetoacetate concentration ratio increased from 1·2 to 8·4 in normal livers, from 2·0 to 2·8 in early fatty livers, from 1·2 to 2·4 in late fatty livers and from 2·1 to 4·0 in cirrhotic livers when ethanol was added to the medium. 6. The effects of ethanol on liver metabolism during the development of dietary cirrhosis are discussed and related to human fatty liver and cirrhosis during chronic ethanol consumption.     

Methylphenidate decreases regional cerebral blood flow in normal human subjects

To assess the effects of methylphenidate (MP) on cerebral blood flow (CBF), 5 healthy males were studied using ¹⁵O-water and positron emission tomography before and after MP (0.5mg/kg iv). MP significantly decreased whole brain CBF at 5–10 minutes (25±11%) and at 30 minutes (20±10%) after its administration. Decrements in CBF were homogeneous throughout the brain (regional decrements 23–30%) and probably reflect the vasoactive properties of MP. The vasoactive properties of MP should be considered when prescribing this drug chronically and/or when giving it to subjects with cerebrovascular compromise.     

Clearance of oxypurines in normal subjects and in gout patients subjected to a purine-free diet. Effects of allopurinol

The clearance of uric acid, hypoxanthine and xanthine has been examined in gout patients and in normal subjects compared to creatinine, after a purine-free diet. The treatment decreased the clearance in normal subjects, but showed an opposite effect in gout patients. The clearances both of uric acid, hypoxanthine and xanthine were enhanced by allopurinol. The interpretation of the observed variations is discussed.     

Comparative study of maximal midexpiratory flow rate in normal smoking and non-smoking subjects

MMF is considered one of the most sensitive parameter to point out initial decay of small airways that should appear prematurely in smokers as compared with non smokers. To verify the above we tested male subjects apparently free from any respiratory disease. They were classed into two groups of equal number: the first group of smokers, the second one of non smokers. We did not find any statistically significant difference between the two groups: this is probably due to the young age of the subjects and consequently to the relative short period of exposure to tobacco smoke.     

Effects of hepatic blood flow on hepatic ethanol kinetics measured in cats and predicted from the parallel tube model

In cats anesthetized with pentobarbital, a long-circuit technique was used to measure hepatic blood flow while portal flow was varied from 0 to 300% of normal in random steps. Arterial, portal, and hepatic venous blood samples were analyzed for ethanol concentrations during continuous infusion of ethanol (20 mumol/(min.kg body weight) into the reservoir. Measured values for logarithmic mean sinusoidal ethanol concentration, hepatic venous ethanol concentration, hepatic ethanol uptake, and ethanol extraction were compared with the values predicted by the parallel tube model for hepatic uptake of substrates using Vmax and Km determined in each cat at the start of the experiment. Measured and predicted values were very similar at all blood flows above 65% control, but statistical regression analysis indicated a small but highly significant deviation of the measured values from the predicted values. At low flows, measured values of logarithmic mean sinusoidal and hepatic venous concentrations markedly exceeded the predicted values in most cats. The results indicate that the parallel tube model, which assumes all sinusoids are identical and equally perfused, provides a useful approximation for the effects of hepatic blood flow on hepatic ethanol kinetics except at low flows. However, there appears to be a significant degree of sinusoidal heterogeneity that results in a better fit to the distributed model. Our previously reported data for hepatic galactose uptake followed a similar pattern when reanalyzed in this more rigorous way.     

Effects of inspiratory flow on diaphragmatic motor output in normal subjects.

Increasing inspiratory flow (V) has been shown to shorten neural inspiratory time (TI(n)) in normal subjects breathing on a mechanical ventilator, but the effect of V on respiratory motor output before inspiratory termination has not previously been studied in humans. While breathing spontaneously on a mechanical ventilator, eight normal subjects were intermittently exposed to 200-ms-duration positive pressure pulses of different amplitudes at the onset of inspiration. Based on the increase in V above control breaths (DeltaV), trials were grouped into small, medium, and large groups (mean DeltaV: 0.51, 1.11, and 1.65 l/s, respectively). We measured TI(n), transdiaphragmatic pressure (Pdi), and electrical activity (electromyogram) of the diaphragm (EMGdi). Transient increases in V caused shortening of TI(n) from 1.34 to 1.10 (not significant), 1.55 to 1.11 (P < 0.005), and 1.58 to 1.17 s (P < 0. 005) in the small, medium, and large DeltaV groups, respectively. EMGdi measured at end TI(n) of the pulse breaths was 131 (P < 0.05), 142, and 155% (P < 0.05) of the EMGdi of the control breaths at an identical time point in the small, medium, and large trials, respectively. The latency of the excitation was 126 +/- 42 (SD) ms, consistent with a reflex effect. Increasing V had two countervailing effects on Pdi: 1) a depressant mechanical effect due primarily to the force-length (11.2 cmH(2)O/l) relation of the diaphragm, and 2) an increase in diaphragm activation. For the eight subjects, mean peak Pdi did not change significantly, but there was significant intersubject variability, reflecting variability in the strength of the excitation reflex. We conclude that increasing inspiratory V causes a graded facilitation of EMGdi, which serves to counteract the negative effect of the force-length relation on Pdi.     

Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heart failure

Isnard, Richard, Philippe Lechat, Hanna Kalotka, HafidaChikr, Serge Fitoussi, Joseph Salloum, Jean-Louis Golmard, Daniel Thomas, and Michel Komajda. Muscular blood flow response to submaximal leg exercise in normal subjects and in patients with heartfailure. J. Appl. Physiol. 81(6):2571-2579, 1996.Blood flow to working skeletal muscle is usuallyreduced during exercise in patients with congestive heart failure. Anintrinsic impairment of skeletal muscle vasodilatory capacity has beensuspected as a mechanism of this muscle underperfusion during maximalexercise, but its role during submaximal exercise remains unclear.Therefore, we studied by transcutaneous Doppler ultrasonography thearterial blood flow in the common femoral artery at rest and during asubmaximal bicycle exercise in 12 normal subjects and in 30 patientswith heart failure. Leg blood flow was lower in patientsthan in control subjects at rest [0.29 ± 0.14 (SD) vs. 0.45 ± 0.14 l/min, P < 0.01], at absolute powers and at the same relative power (2.17 ± 1.06 vs. 4.39 ± 1.4 l/min, P < 0.001). Because mean arterial pressure was maintained, leg vascularresistance was higher in patients than in control subjects at rest (407 ± 187 vs. 247 ± 71 mmHg ^· l^{1 ·} min,P < 0.01) and at thesame relative power (73 ± 49 vs. 31 ± 13 mmHg ^· l^{1 ·} min,P < 0.01) but not at absolutepowers. Although the magnitude of increase in leg blood flow correctedfor power was similar in both groups (31 ± 10 vs. 34 ± 10 ml ^· min^{1 ·} W¹),the magnitude of decrease of leg vascular resistance corrected forpower was higher in patients than in control subjects (5.9 ± 3.3 vs. 1.9 ± 0.94 mmHg ^· l^{1 ·} min ^· W¹,P < 0.001). These results suggestthat the ability of skeletal muscle vascular resistance to decrease isnot impaired and that intrinsic vascular abnormalities do not limitvasodilator response to submaximal exercise in patients with heartfailure.

     

Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Alterations in the metabolism of monoamine neurotransmitters have been proposed to be involved in the development of the hepatic encephalopathy (HE) associated with experimental and human liver failure. In order to evaluate this hypothesis, the monoamines and some of their metabolites were measured in homogenates of caudate nucleus (CAU), prefrontal (PFCo) and frontal cortex (FCo) dissected from brains obtained at autopsy from nine cirrhotic patients who had died in hepatic coma and an equal number of control subjects, free from neurological, psychiatric and hepatic disorders, matched for age and time interval from death to freezing of autopsied brain samples. Monoamine measurements were performed by high-performance liquid chromatography with ion-pairing and electrochemical detection after a simple extraction procedure. In all three regions investigated, concentrations of dopamine (DA) were unchanged in cirrhotic patients vs controls while its metabolites, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) were selectively affected i.e.3-MT was found to be increased in CAU, while HVA levels were increased in FCo and CAU. DOPAC was also found to be unchanged in CAU. Noradrenaline (NA) levels were greatly increased in PFCo and FCo of cirrhotic patients but remained unchanged in CAU. No significant differences in the concentrations of either serotonin (5-HT) or of its precursor 5-hydroxytryptophan (5-HTP) were found in any of the three regions studied. However, 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, was increased in PFCo and CAU of cirrhotic patients. These findings show that selective alterations of catecholamine and 5-HT systems are involved in human HE and therefore, they may play an important role in the pathogenesis of certain neurological symptoms associated with this encephalopathy.