Metabolism of phenylalanine in liver diseases

Summary 1. Amethod for the determination of phenylalaninehydroxylase-activity in needle biopsy material of human liver was developed and tested. The kinetic data of the enzyme were determined. TheK _m for the substrate phenylalanine is 1,32 mM, for the cofactor 0,08 mM.2. The activity of phenylalaninehydroxylase was determined in biopsies from normal liver, liver cirrhosis, alcoholic hepatitis and other liver diseases. In all liver diseases the enzyme activity related to wet weight or DNA is reduced. The capacity for the hydroxylation of phenylalanine (of a cirrhotic liver) amounts to about 20% of normal liver.3. After an oral load with L-phenylalanine (100 mg/kg) the phenylalanine- and tyrosine-concentration in blood plasma was followed for 5 hours. Patients with liver cirrhosis or acute hepatitis show significant higher concentrations of phenylalanine, and significant lower concentrations of tyrosine than normal persons.4. From the decline of phenylalanine-concentration after the maximum the phenylalanine-elimination rate and from the increase of tyrosine concentration the tyrosine-production rate were calculated. Between phenylalanine-elimination rate and tyrosine-production rate a strong correlation exists. In patients with cirrhosis or acute hepatitis significantly reduced phenylalanine-elimination rate and tyrosine production rate were found compared with persons without liver disease. Patients with alcoholi hepatitis show no significant difference compared with normal persons.5. There is no correlation between the activity of phenylalaninehydroxylase in liver tissue and phenylalanine-elimination rate and tyrosine-production rate, respectively, calculated from the concentration of this amino acids in serum after a phenylalanine load.6. We conclude from these findings that the increased serum concentration of phenylalanine in some liver diseases, especially liver cirrhosis, can partly be explained by the diminished metabolism of phenylalanine in the liver. Portocaval shunts probably contribute to the elevated level of phenylalanine in serum.Mit Unterstützung der Deutschen Forschungsgemeinschaft und der Sandoz-Stiftung für medizinische Forschung     

The effects of clonidine on human digital vasculature

Large concentrations of alpha(2) agonists cause vasoconstriction. However, the threshold of the vasoconstrictive effect in humans is not known. We studied seven volunteers to determine the lower limit of the vasoconstrictive effect of clonidine. Subjects were studied while they were awake, and they were anesthetized with propofol/alfentanil/N(2)O. Arterial blood pressure was continuously monitored via radial arterial catheter and vasoconstriction via finger volume plethysmography measuring infrared light transmitted through a fingertip (LTF). Clonidine was administered, targeting plasma clonidine concentrations of 0.3, 0.45, 0.68, 1.0, 1.5, and 2.25 ng/mL. The maximum change from preclonidine values for systolic blood pressure (SBP) and LTF was analyzed by using repeated measures analysis of variance. In awake subjects, clonidine (2.25 ng/mL) decreased LTF by 14%+/-13% and SBP from 141+/-7 to 110+/-15 mm Hg (P<0.0001). In contrast, clonidine (2.25 ng/mL) increased LTF in anesthetized subjects by 21%+/-16% and SBP from 91+/-7 to 106+/-19 mm Hg (P<0.0001). We conclude that the same dose of clonidine that decreased blood pressure and caused vasodilation in awake subjects had the opposite effect in anesthetized subjects with reduced sympathetic tone, increasing blood pressure and causing vasoconstriction in human digital vasculature. Our findings suggest that the lower threshold for clonidine-induced vasoconstriction in human digital vasculature is 1.0 ng/mL.     

Influence of steroids on urea-cycle enzymes in chronic human liver disease

Summary Activities of Krebs-Henseleit enzymes were determined in liver biopsies of normal persons and in patients suffering from alcoholic hepatitis and chronic active hepatitis. Prednisone was administered for five days in falling dosis (1.5 mg–0.5 mg/kg/body weight) to patients with alcoholic hepatitis and to controls. Patients with chronic active hepatitis received 15–20 mg prednisone daily for more than three months.In healthy persons prednisone did not influence the activities of Krebs-Henseleit enzymes.In patients with alcoholic hepatitis most of the urea-cycle enzymes are significantly decreased (p<0.05) when compared to controls. After glucocorticoid administration enzyme activities remained unchanged.Activities of most of the urea-cycle enzymes are significantly (p<0.05) decreased in untreated patients with chronic active hepatitis.In some of these patients, glucocorticoid administration was associated with a remission as proved by clinical, biochemical and histological data.Activities of the rate-limiting enzymes of the ureacycle (ASAS, CPS) increased significantly in these patients.By contrast, alterations of enzyme activities could not be observed in patients who failed to respond favourably to steroid treatment.     

Effect of dexmedetomidine, an alpha2-adrenoceptor agonist, on human pupillary reflexes during general anaesthesia

AIMS: To test the hypothesis that the alpha2-adrenergic agonist, dexmedetomidine, dilates the pupil and does not alter the pupillary light reflex of anaesthetized patients. METHODS: Eight volunteers were administered general anaesthesia with propofol, nitrous oxide and alfentanil. One hour and 25 min after induction of anaesthesia, a 45 min infusion of dexmedetomidine was begun, targeting a plasma concentration of 0.6 ng x ml(-1). Pupil size, pupillary light reflex amplitude, light reflex recovery time, and reflex dilation were measured before and during dexmedetomidine infusion. RESULTS: Dexmedetomidine produced no change in pupil size and light reflex recovery time, increased the light reflex from 0.30 +/- 0.14 to 0.37 +/- 0.12 mm and significantly reduced pupillary reflex dilation by 72 +/- 62%. CONCLUSIONS: These pupillary effects of dexmedetomidine in humans are difficult to reconcile with the findings obtained in cats and rats that have demonstrated a direct inhibitory effect of alpha2-adrenergic agonists on the pupilloconstrictor nucleus. The increase in the magnitude of the light reflex in response to dexmedetomidine does not necessarily involve an anxiolytic mechanism.     

Effect of α2B-Adrenoceptor Polymorphism on Peripheral Vasoconstriction in Healthy Volunteers

Background: Alpha-2B adrenoceptor is the vasoconstrictive subtype in the mouse. Human [alpha]2B-AR deletion (D) allele has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction on [alpha]2 activation. The goal of this study was to test the hypothesis that [alpha]2B-adrenoceptor activation induces enhanced vasoconstriction in carriers of the DD genotype, compared with carriers of the insertion/insertion (II) genotype.

Methods: The authors administered increasing doses of dexmedetomidine (targeting plasma concentrations of 0.15, 0.3, 0.6, and 1.2 ng/ml) to 16 healthy young volunteers (8 carrying the [alpha]2B DD genotype, 8 carrying the II genotype) in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmitted through a finger, finger blood flow by venous occlusion plethysmography, and hemodynamic variables.

Results: All concentration of dexmedetomidine increased light transmitted through the finger (vasoconstriction) and systolic blood pressure and decreased heart rate in both groups (P < 0.001 for all). Dexmedetomidine reduced finger arterial inflow only in the DD group (P < 0.001). Dexmedetomidine had no effect on finger venous outflow or venous capacitance. There were no significant differences between the II and DD groups in any of the variables.     

Measurement of systolic blood pressure using pulse oximetry during helicopter flight

OBJECTIVE: Monitoring of vital signs in critically ill patients during helicopter flight is difficult because of the noise and vibrations of the aircraft. We evaluated the use of a pulse oximeter to measure systolic BP intraflight. DESIGN: Systolic BP measured by pulse oximetry was compared with systolic BP measured by the direct intra-arterial and the arterial occlusion methods intraflight. Systolic BP by pulse oximetry was measured by observing the return of the plethysmographic waveform of the pulse oximeter as the BP cuff ipsilateral to the pulse oximeter probe was slowly deflated. Arterial occlusion pressure was measured by observing the return of the intraarterial waveform as the BP cuff ipsilateral to the arterial cannula was slowly deflated. SETTING: The study was performed during patient transport, intraflight. PATIENTS: Ten critically ill patients were studied. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Seventy-three sets of measurements were recorded. The best correlation (r2 = .99) was found between pulse oximetry and the arterial occlusion method. The indirect methods correlated better with each other than with direct intraarterial measurements. The noise and the vibrations of the helicopter did not significantly interfere with the operation of the pulse oximeter. CONCLUSIONS: We conclude that a pulse oximeter that displays a plethysmographic waveform can accurately measure systolic BP intraflight.     

Isozymes of Aspartate Aminotransferase in Rat Liver during Acute Uraemia

Abstract. Total activity of aspartate-aminotransferase (GOT; EC 2.6.1.1) and activities of the cytoplasmic (c-GOT) and mitochondrial (m-GOT) isozymes were measured in rat liver 24 and 48 h after bilateral nephrectomy.
24 h after nephrectomy no significant differences in enzyme activities could be detected between uraemic animals and sham-operated controls. However 48 h after nephthrectomy the total activity of GOT increased significantly. Fractional tissue extraction revealed an elevation of only the cytoplasmic isozyme (c-GOT), due to a selective increase of this enzyme fraction. No significant change could be noticed of the mitochondrial isozyme (m-GOT). These results are discussed with regard to an increased gluconeogenesis in rat liver 48 h after bilateral nephrectomy.