Cardiovascular responses in paraplegic subjects during arm exercise

Summary The purpose of this study was to examine cardiovascular responses during arm exercise in paraplegics compared to a well-matched control group. A group of 11 male paraplegics (P) with complete spinal cord-lesions between T6 and T12 and 11 male control subjects (C), matched for physical activity, sport participation and age performed maximal arm-cranking exercise and submaximal exercise at 20%, 40% and 6070 of the maximal load for each individual. Cardiac output (Q _c) was determined by the CO₂ rebreathing method. Maximal oxygen uptake was significantly lower and maximal heart rate (f _c) was sigificantly higher in P compared to C. At the same oxygen uptakes no significant differences were observed inQ _c between P and C; however, stroke volume (SV) was significantly lower andf _c significantly higher in P than in C. The lower SV in P could be explained by an impaired redistribution of blood and, therefore, a reduced ventricular filling pressure, due to pooling of venous blood caused by inactivity of the skeletal muscle pump in the legs and lack of sympathetic vasoconstriction below the lesion. In conclusion, in P maximal performance appears to have been limited by a smaller active muscle mass and a lower SV despite the higher _c,max. During submaximal exercise, however, this lower SV was compensated for by a higherf _c and, thus at the same submaximal oxygen uptake,Q _c was similar to that in the control group.     

Changes in ultrastructure of hepatocytes and liver test results before,during, and after treatment with interferon-β in patients with HBeAg-positive chronic active hepatitis

We studied the histological and ultrastructural changes in the liver and alterations in the liver test results before, during, and after treatment with human interferon- from five patients with hepatitis B e antigen-positive chronic active hepatitis. A daily dose of 3×10⁶ to 6×10⁶ units of interferon- was given intravenously for four weeks. The total index of periportal and portal inflammation, intralobular degeneration, and focal necrosis before treatment was decreased significantly six months after treatment (P<0.05). Ultrastructurally, the structure of endoplasmic reticulum was irregularly shaped or fragmentally decreased during treatment, but these disappeared six or 12 months after treatment. Glycogen particles diminished greatly during treatment. The alanine aminotransferase concentrations in these patients increased during treatment. Serum albumin and cholinesterase levels decreased significantly at the fourth week of treatment (P<0.01) and at the third day (P<0.01) to the second week (P<0.05) of treatment, respectively. These results suggest that interferon- injures endoplasmic reticulum and glycogen areas and damages the cholinesterase activity in the early stage of treatment and protein synthesis in patients with hepatitis B e antigen-positive chronic active hepatitis.     

Fifty years of research onN-acetyl-2-aminofluorene,one of the most versatile compounds in experimental cancer research

Summary It is just about 50 years since the publication of the report on the toxicity and carcinogenicity of the potent carcinogenN-acetyl-2-aminofluorene (AAF). In 1940 very few reports on the carcinogenic activity of chemical compounds in experimental animals were available. The discovery of pure chemicals as carcinogens, such as AAF, azo dyes and benzo[a]pyrene, provided cancer researchers with a number of tools whereby the progressive changes involved in the induction of cancer could be studied in experimental systems. Contrary to the results with other carcinogens then known, AAF induced numerous types of tumors, but not at the site of application. This finding stimulated a great deal of interest in its use as an experimental carcinogen to study its metabolic fate and mechanism of action. During the following years an ever increasing number of reports appeared on the carcinogenicity of AAF in various species, on its metabolic fate, on the interaction of reactive metabolites with nucleic acids and proteins, and on its mutagenic activity. Particularly studies on the metabolism of AAF and the interaction with nucleic acids have contributed appreciably to our understanding of the mechanism of action of aromatic amines and also of other chemical carcinogens. It can be expected that AAF and its derivatives will continue to be used for specific applications in experimental cancer research. One of the most recent achievements is the preparation of site-specific AAF- and aminofluorene-modified DNA sequences for mutagenesis studies.Abbreviation AAF N-acetyl-2-aminofluorenem The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author The Editors     

Plasminogen activation in plasma of patients with systemic lupus erythematosus

Summary We measured ₂-plasmin inhibitor-plasmin complexes (PI-PC) in plasma of patients with systemic lupus erythematosus (SLE) to examine the plasminogen activation in SLE. The plasma PI-PC level in 23 patients with SLE was significantly higher than that in 18 normal subjects (P<0.001) and the SLE patients with nephrotic syndrome had higher plasma PI-PC levels than those without nephrotic syndrome (P<0.01). In addition, the plasma PI-PC level was significantly correlated with the level of plasma C3 breakdown products (iC3b/C3dg) in the patients with SLE (r=0.53, P<0.01). These results suggest that plasminogen is activated in plasma of patients with SLE and that the plasminogen activation may be associated with the activation of complement in SLE.     

Measurements of CO2 reactivity and barbiturate reactivity in patients with severe head injury

Summary In nine patients with severe head injury subjected to continuous hyperventilation and barbiturate coma treatment with pentobarbitone, the regional cerebral blood flow was measured as initial slope index (ISI) with a 32 channel Cerebrograph, and cerebral metabolic rate of oxygen (CMRO₂) was calculated as the product of mean global CBF and the arterio-venous oxygen content difference.CBF was measured at strategic intervals either to follow the treatment (hyperventilation and/or pentobarbitone), or to determine whether these principles of treatment should be intensified or reduced. During the flow measurements the CO₂ reactivity and the reactivity to a bolus injection of thiopentone 5 mg/kg were calculated globally and regionally. The global CO₂ reactivity was calculated as relative (%change CBF/PaCO₂ mmHg) and absolute (CBF/ PaCO₂ mmHg), and the reactivity to barbiturate was calculated globally as CMRO₂, and regionally as %change rCBF.The absolute and relative global CO₂ reactivities correlated positively with the mean. CBF values before hyperventilation, and the global barbiturate reactivity was dependent on the CMRO₂ value obtained before hyperventilation. However, at low levels of CMRO₂ ranging between 1.0 and 1.1 ml O₂ the barbiturate reactivity was abolished. The regional studies of CBF, CMRO₂, CO₂ reactivity and barbiturate reactivity gave important information, when decisions concerning therapeutic regimes with special reference to hyperventilation and sedation with pentobarbitone were necessary.     

Comparative study of suture and laser-assisted anastomoses in rat sciatic nerves

Conventional suture repair of peripheral nerves results in a fibrotic reaction that is detrimental to nerve regeneration. As an alternative procedure known as "laser-assisted" repair, a laser can be used, along with a reduced number of sutures, to reanastomose served peripheral nerves. To explore the long-term implications of this technique, the right sciatic nerves of Sprague-Dawley rats were surgically cut and reanastomosed either by means of four epineurial sutures or two epineurial sutures and CO2 laser welds. Tensile strength, electrophysiology, histology, and functional studies were performed up to 11 months postoperatively. Tensile strength measurements indicate no long-term disadvantage with the laser-assisted technique, although the short-term tensile strength is lower than with conventional suture repair. The conduction velocities of the repaired nerves were similar for both techniques; however, laser-assisted repaired nerves were found to have lower stimulation thresholds and reduced branching compared to the suture repaired nerves. The measured functional recovery was similar for both repair techniques.     

Effects of lysophosphatidylcholine and arachidonic acid on the regulation of intracellular Ca2+ transport

Summary The role of lysophosphatidylcholine and arachidonic acid in signal transduction was investigated using subcellular organelles and permeabilized cells from liver. Both substances can be generated intracellularly by the action of phospholipase A₂ on phosphatidy1choline. Lysophosphatidylcholine as well as arachidonic acid raised the free Ca²⁺ concentration in the incubation media of permeabilized cells, isolated mitochondria and microsomes. The half maximally effective concentrations for Ca²⁺ release from mitochondria were 78 ± 1 mol/l for lysophosphatidylcholine and 80 ± 11 mol/l for arachidonic acid. Though isolated microsomes released Ca²⁺ in response to both agents, the combined presence of mitochondria and microsomes did not exhibit a synergism in Ca²⁺ release in response to arachidonic acid; the increase in the free Ca²⁺ concentration in response to lysophosphatidylcholine was even smaller than with mitochondria alone. It is concluded that the two reaction products of phospholipase A₂ can raise the cytoplasmic Ca²⁺ concentration and therefore may participate in cellular signal transduction. Send offprint requests to I. Rustenbeck at the above address     

Involvement of adenylate cyclase and protein kinase C in the α2-adrenoceptor-mediated inhibition of noradrenaline and 5-hydroxytryptamine release in rat hypothalamic slices

Summary In superfused rat hypothalamic slices prelabelled with [³H]-noradrenaline, the ₂-adrenoceptor agonist UK 14304 inhibited in a concentration-dependent manner the electrically-evoked release of tritium. This inhibition was antagonized by the ₂-adrenoceptor blocking agent idazoxan, which by itself increased the electrically-evoked tritium overflow. Exposure to forskolin, an adenylate cyclase activator, increased the electrically-evoked release of [³H]-noradrenaline. In the presence of forskolin (1 mol/l), both the inhibitory effect of UK 14304 and the increasing effect of idazoxan on the electrically-evoked release of [³H]-noradrenaline were less pronounced than in the absence of the adenylate cyclase activator. Exposure to forskolin and to the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine shifted to the right the concentration-effect curve for UK 14304 in a similar manner as that observed in the presence of forskolin alone. Exposure to phorbol-12,13-dibutyrate (0.01–10 mol/l), a drug which activates protein kinase C, increased the electrically-evoked release of [³H]-noradrenaline. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mol/l), the concentration effect curve for UK 14304 on tritium overflow was significantly shifted to the right. The increasing effect of idazoxan on tritium overflow was significantly less pronounced in the presence of 1 mol/l phorbol-12,13-dibutyrate.In superfused rat hypothalamic slices prelabelled with [³H]-5-hydroxytryptamine, the ₂-adrenoceptor agonist UK 14304 significantly inhibited the electrically-evoked release of tritium. Exposure to forskolin increased in a concentration-dependent manner [³H]-5-hydroxytryptamine overflow, but did not modify the UK 14304-mediated inhibition. Exposure to 3-isobutyl-1-methylxanthine enhanced the electrically-evoked release of [³H]-5-hydroxytryptamine. In the presence of both forskolin (1 mol/l) and 3-isobutyl-l-methylxanthine (1 mmol/l), the concentration-response curve for UK 14304 was significantly shifted to the right. Exposure to phorbol-12,13-dibutyrate (0.01–10 mol/l) enhanced in a concentration-dependent manner the electrically-evoked overflow of [³H]-5-hydroxytryptamine. In the presence of phorbol-12,13-dibutyrate (0.1 and 1 mol/l), UK 14304 was significantly less potent to inhibit tritium release than in the absence of the protein kinase C activator.It is concluded that both cyclic AMP and phosphoinositide turnover are involved in the modulation of noradrenaline and 5-hydroxytryptamine release by presynaptic ₂-adrenoceptors in rat hypothalamic slices. However, these interactions do not represent definitive proof for a cause-effect relationship for the second messengers mediating the ₂-adrenoceptor induced inhibition of transmitter release either as autoreceptor or as heteroreceptor.Send offprint requests to S. Z. Langer at the above address     

Phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex

Summary Possible antagonist effects of phentolamine at presynaptic serotonin autoreceptors were studied in slices of the occipito-parietal cortices of the rabbit and the rat. The slices were preincubated with ³H-serotonin and then superfused and stimulated electrically with single pulses or pulse trains. Nitroquipazine 1 mol/l, a compound that inhibits the high affinity neuronal uptake of serotonin, was present in the superfusion medium in all one pulse-experiments as well as in experiments in which the effect of unlabelled serotonin was examined.In rabbit cortical slices, unlabelled serotonin reduced the single pulse-evoked overflow of tritium. Its concentrationresponse curve was not changed by the selective ₂-adrenoceptor antagonist idazoxan 1 mol/l but was shifted to the right by phentolamine 1 and 10 mol/l. Phentolamine 10 mol/l also shifted to the right the concentration-inhibition curve of the selective 5-HT₁-receptor agonist 5-carboxamidotryptamine. When the slices were stimulated by trains of 30 pulses at 3 Hz, phentolamine 1 and 10 mol/l but not 0.1 mol/l increased the evoked overflow of tritium, the maximal increase amounting to 178%; its effect was enhanced in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l (a drug combination that, when given alone, slightly increased the evoked overflow of tritium). The serotonin receptor antagonist metitepin at concentrations of 0.01–1 mol/l also increased the overflow of tritium elicited by 30 pulses/3 Hz, the maximal increase amounting to 280%; its effect was potentiated in the presence of nitroquipazine 1 mol/l plus idazoxan 10 mol/l but was abolished or almost abolished in the presence of nitroquipazine 1 mol/l plus phentolamine 10 mol/l (a drug combination that, given alone, greatly increased the evoked overflow of tritium). When slices were stimulated by trains of 360 pulses at 3 Hz, there was no apparent antagonism of phentolamine 10 mol/l against the inhibitory effect of unlabelled serotonin. In rat brain cortex slices, unlabelled serotonin reduced the overflow of tritium elicited by 4 pulses delivered at 100 Hz. Again, phentolamine 10 mol/l shifted the concentration-response curve to the right.It is concluded that phentolamine blocks presynaptic serotonin autoreceptors in rabbit and rat brain cortex with pA₂ values of 6.44 and 5.95, respectively. Previous failures to detect the antagonistic effect against exogenous agonists were probably due to stimulation conditions that led to marked endogenous autoinhibition of serotonin release. At least the major part of the increase by phentolamine of the release of serotonin is due to autoreceptor blockade rather than blockade of the presynaptic a2-adrenoceptors at the cortical serotoninergic axons.Send offprint requests to N. Limberger at the above address     

Uptake inhibitors do not change the effect of imidazoline α2-adrenoceptor agonists on transmitter release evoked by single pulse stimulation in mouse vas deferens

Summary The present study was undertaken to compare the presynaptic interaction of neuronal noradrenaline uptake inhibitors with imidazoline and phenylethylamine ₂adrenoceptor agonists under two different conditions: at low and high noradrenaline concentrations in the biophase.Isolated mouse vasa deferentia were stimulated with trains of 7 pulses given at 0.2 Hz and the inhibition by the ₂-adrenoceptor agonists clonidine, -methylnoradrenaline, and UK-14,304 of twitch responses was measured in the absence and in the presence of either cocaine (12 mol/l) or desipramine (40 nmol/l). The effects were determined for the first (equivalent to single pulse stimulation) and the last stimulus of each train. Both uptake inhibitors antagonized the presynaptic inhibitory effects of imidazolines (clonidine and UK-14,304) on the last twitch; the effects on the first twitch remained unchanged. In contrast, the uptake inhibitors potentiated the inhibitory effect of the phenylethylamine (-methylnoradrenaline) on both the first and the last twitches.These results support the view that the concentration of noradrenaline in the biophase plays a decisive role in the inhibition by a₂-adrenoceptor agonists of the electrically evoked release of noradrenaline. Agonists that are not substrates of neuronal uptake (i.e., clonidine, UK-14,304) become less effective when noradrenaline is present in the biophase while substrates of neuronal uptake (i. e., -methylnoradrenaline) do not. The results argue against the hypothesis that uptake inhibitors interact directly with presynaptic ₂-adrenoceptors or act at some link between uptake and receptor sites. Send offprint requests to S. Guimarães at the above address