Enflurane alters compensatory hemodynamic and humoral responses to hemorrhage.

This study examined the impact of enflurane (3%) on the hemodynamic and humoral defense mechanisms in a canine model of hemorrhagic shock. In order to obtain reasonable reference values with confounding influences of anesthesia and recent surgical preparation, the dogs were chronically instrumented 8-10 days prior to the experiments enabling measurements in the conscious state. While arterial pressure, cardiac output, and the corresponding derivatives were recorded continuously, plasma catecholamines and plasma renin activity were determined intermittently. As anticipated, the conscious dogs were able to tolerate considerable more severe levels of hemorrhage than the dogs anesthetized with enflurane. This finding is associated with reciprocal responses of both the renin-angiotensin system and the sympathoadrenal system in the conscious and anesthetized states. While the sympathoadrenal system prevailed in the conscious dogs, the renin-angiotensin system predominated during enflurane anesthesia. Despite the augmented response of the renin-angiotensin system, the activation of this defense mechanism was not sufficiently powerful enough to prevent overall hemodynamic deterioration with hemorrhage in the animals anesthetized with enflurane.

B-HT 920 and B-HT 958: presynaptic effects on electrically evoked 3H-dopamine release from slices of rat nucleus accumbens.

The effects of two thiazoloazepine derivatives, B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine) and B-HT 958 (2-amino-6-(p-chloro-benzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]a zepine) on electrically evoked overflow of 3H-dopamine were studied. Slices from nucleus accumbens of the rat were preincubated with 3H-dopamine and superfused at 23 degrees C or 37 degrees C. Electrical field stimulation was applied using frequencies of 0.5 or 5 Hz. At 37 degrees C/5 Hz, B-HT 920 markedly and dose-dependently (0.01-0.1 mumol/l) reduced the stimulation evoked overflow of tritium. Its dose-response curve was shifted to the right at 23 degrees C/0.5 Hz and 23 degrees C/5 Hz, respectively. A similar result was obtained with the dopamine receptor agonist, apomorphine (1 mumol/l). B-HT 958 (0.1-10 mumol/l) also reduced electrically induced overflow of tritium at 37 degrees C/5 Hz, had no effect at 23 degrees C/0.5 Hz, and facilitated tritium overflow at 23 degrees C/5 Hz. Sulpiride (10 mumol/l) completely prevented the effects of B-HT 920 (1 mumol/l) or B-HT 958 (1 mumol/l) at 37 degrees C/5 Hz, whereas phentolamine (1 mumol/l) had no effect on the actions of the two drugs under these experimental conditions. From the patterns of effects obtained under the different experimental conditions it is concluded that B-HT 920 acts as full agonist at presynaptic dopamine autoreceptors whereas B-HT 958 acts as partial agonist.

Effects of clonidine on the stimulation-evoked release of 3H-noradrenaline from superfused rat brain slices as a function of the biophase concentration. Temperature dependent widening of extracellular space.

The influence of clonidine on the stimulation-evoked overflow of tritium was studied in brain slices preincubated with 3H-noradrenaline. The slices were prepared from parietal cortex (Cx), nucleus anterior hypothalami (nah) and nucleus tractus solitarii (nts). After preincubation, the tissues were superfused at 23 degrees C or 37 degrees C with a medium containing the noradrenaline uptake inhibitor desipramine. Electrical field stimulation was applied using stimulation frequencies of 0.3-10 Hz. At 23 degrees C/0.3 Hz, clonidine concentration-dependently inhibited the evoked overflow of tritium in all three brain regions. In contrast, at 23 degrees C/3 Hz the inhibitory effect of the drug in the Cx was abolished and a facilitation was observed in the nah and nts. When tested at increasing frequencies of stimulation in the nts at 23 degrees C, clonidine exerted a dual action, characterized by a reduction of electrically evoked responses at frequencies below 1 Hz and a facilitation at frequencies above 1 Hz. At 37 degrees C, clonidine concentration-dependently decreased the evoked overflow in all brain regions studied, this effect being more pronounced at 0.3 Hz than at 3 Hz. The apparent lack of an effect of clonidine on the stimulation-evoked overflow of tritium in the Cx at 23 degrees C/3 Hz was turned to a facilitation when noradrenaline (0.01 mumol/l) was included in the superfusion medium. Conversely, an inhibitory effect of clonidine was seen when the uptake blocker desipramine (as well as noradrenaline) was omitted from the superfusion medium.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of morphine on circulatory control in acute progressive hemorrhage]. / Einfluss von Morphin auf die Kreislaufkontrolle bei akuter progressiver Hämorrhagie.

The effects of acute, progressive haemorrhage, 1 ml/s were examined in the same mongrel dogs on separate days, unanaesthetized and anaesthetized with morphine (2 mg/kg i.v.) and with administration of nasal oxygen to maintain arterial blood gases at physiological levels. In normal, unanaesthetized dogs mean arterial pressure was well maintained through 30 ml/kg of blood loss. Cardiac output fell with haemorrhage (70 +/- 2%; mean +/- S.E.M.) but heart rate and total peripheral resistance rose by 72 +/- 11% and by 124 +/- 11%, respectively. Morphine induced slight but significant changes in heart rate and mean arterial pressure but did not affect the ability to withstand hemorrhage. Thus, in contrast to barbiturates and volatile anaesthetics, morphine does not seem to comprise the efficacy of the rapidly acting pressure control system in response to progressive hemorrhage. The results of the present investigation are not consistent with the hypothesis that opioids are hypotensive factors in hypovolaemic shock.

Acute effects of alinidine on heart rate and blood pressure in healthy subjects and patients with hyperkinetic heart syndrome.

The effects of a single dose of alinidine (0.5 mg/kg i.v.), the N-allyl-derivative of clonidine, on heart rate and blood pressure were investigated in healthy volunteers and in patients with hyperkinetic heart syndrome, at rest and during bicycle exercise. In healthy volunteers plasma catecholamine levels were also determined. Alinidine did not change heart rate at rest in the healthy volunteers but it did significantly reduce exercise-induced tachycardia, whereas blood pressure and plasma catecholamine levels were not significantly affected by alinidine, either at rest or during exercise. In patients with hyperkinetic heart syndrome, alinidine reduced heart rate at rest and during exercise to a similar extent as propranolol (0.1 mg/kg i.v.). The blood pressure did not change with alinidine but it was significantly reduced by propranolol. The observation that an alinidine-induced reduction of heart rate occurs without a concomitant fall in blood pressure, and without a clonidine-like symphatho-inhibitory action, is in line with experimental findings suggesting a specific bradycardic action of alinidine under short-term conditions.

[Double-blind comparative trial of lonazolac-Ca versus naproxen in spinal osteoarthrosis, coxarthrosis and gonarthrosis (author's transl)]. / Vergleich von Lonazolac-Ca mit Naproxen bei vertebragenen Syndromen und bei Arthrosen der grossen Gelenke: Ergebnisse einer Doppelblindstudie.

Two groups of patients, each consisting of 20 patients suffering from spinal osteoarthrosis, coxarthrosis or gonarthrosis participated in a double-blind comparative trial. They received either Lonazolac-Ca (200 mg three times daily) or Naproxen (250 mg twice daily plus 1 placebo capsule in between doses) for three weeks. The therapeutic response was assessed by monitoring pain intensity at rest and on exercise, joint tenderness and joint movement, muscular tension, morning stiffness and walking ability. In spinal osteoarthrosis vertebral flexibility was also measured. Nine out of 11 parameters showed significant improvement with Lonazolac-Ca, whereas only 6 out of 11 improved with Naproxen. However, no clinically relevant differences were recorded between both medications. Laboratory tests in both treatment groups revealed no changes in haematological or biochemical parameters nor in urinanalysis results. Drug-related gastro-intestinal side effects were observed in 2 patients of each treatment group. The patients on Lonazolac-Ca tolerated their medication with the aid of concomitant antacids whereas Naproxen had to be discontinued. One case of dermatitis, which was probably not drug-related was observed in each group. One patient suffering from migraine experienced vertigo and headache on taking Lonazolac-Ca; although this was probably not drug-related medication was discontinued.

Sedimentation and release properties of P2 fractions derived from rat cerebral cortex slices incubated with radiolabeled GABA for a short or long time period.

On homogenization of rat cerebral cortex slices previously incubated with [3H] GABA or [14C]GABA for 5 or 30 min, respectively, particles were recovered in P2 fractions which exhibited similar buoyant density, but different sedimentation velocity on linear sucrose density gradient centrifugation. The K+-evoked release of [3H]GABA from particles isolated from slices previously incubated for 5 min with [3H]GABA was increased in the presence of exogenous Ca2+. In contrast, the K+-evoked release from particles isolated from slices previously incubated for 30 min with [3H]GABA, was not influenced by the presence of exogenous Ca2+. These results suggest that, depending on the incubation time of slices, exogenously applied GABA can be detected in different pools. These pools not only seem to differ in their CA2+ dependency of K+-evoked release but also in their subcellular localization.

Effects of antidepressant treatment with clomipramine on hormonal responses to thyrotropin-releasing hormone and insulin-induced hypoglycemia: implications for the "monoamine-hypothesis".

Neuroendocrine test were carried out to study effects of clomipramine treatment in 24 unipolar depressed women. Clomipramine (50-150 mg/day) increased the response of prolactin and thyrotropin to stimulation by thyrotropin-releasing hormone (TRH), while no response of growth hormone (HGH) to TRH was seen. Clomipramine decreased the response of HGH to insulin, while the responses of prolactin and cortisol to insulin were not affected. The findings suggest that the neuroendocrine and antidepressant effects of clomipramine cannot be accounted for entirely on the basis of monoaminergic mechanisms.

Reduction of [3H]muscimol binding sites in rat dorsal spinal cord after neonatal capsaicin treatment.

Two-day-old rats were pretreated with 50 mg/kg of capsaicin. After 3--4 months, specific binding of [3H]muscimol and [3H]strychnine was measured in membrane preparations from dorsal spinal cord. A 20-30% decrease of the number of [3H]muscimol binding sites was observed after capsaicin treatment. In contrast, [3H]strychnine binding was unchanged. The results provide indirect evidence for a presynaptic location of GABA receptors on capsaicin-sensitive primary afferent neurons.

In vitro modulation by SQ 20009 and SQ 65396 of GABA receptor binding in rat CNS membranes.

SQ 20009 and SQ 65396, two new pyrazolopyridines with anxiolytic properties in animals, reversibly increased Na+-independent 3H-GABA binding to rat cerabral cortex membranes in vitro. This modulation was partially chloride dependent and sensitive to Triton-X 100. Kinetic analysis of 3H-muscimol binding revealed an increase of the apparent number of binding sites. The results are compatible with a functional association between Na+-independent GABA binding sites and the GABA/benzodiazepine receptor complex.

[The influence of mode of delivery on retroplacental and peripheral serum concentrations of HPL and SP-1 (author's transl)]. / Der Einfluss der Entbindungsart auf die retroplazentare und periphere Serumkonzentration von HPL und SP-1.

The concentrations of HPL and SP-1 were measured in retroplacental and peripheral serum in patients who had an elective Caesarean section and in patients who had a spontaneous vaginal delivery. The peripheral concentration of HPL was significantly lower after vaginal delivery than after elective Caesarean sections (p < 0.001). The retroplacental concentration of serum-SP-1 after vaginal delivery was significantly higher than after elective Caesarean section (p < 0.001). After elective Caesarean section the retroplacental concentration of SP-1 was significantly lower than the peripheral concentration (p < 0.001), but after vaginal delivery the mean retroplacental and peripheral serum-SP-1 values were about equal.

[Experimental changes of GABA receptor binding in the central nervous system (author's transl)]. / Experimentelle Beeinflussung der GABA-Rezeptorbindung im Zentralnervensystem.

The effects of etazolate and cartazolate, two pyrazolopyridine derivatives with anxiolytic actions, on the receptor binding of gamma-aminobutyric acid (GABA) was studied in vitro using membrane fractions prepared from rat brain. Both compounds increased the specific GABA receptor binding. This effect was markedly enhanced in the presence of several anions, predominantly halide ions. Pyrazolopyridines appear to modulate the binding properties of GABA receptors by acting on a site closely related to the chloride ion channel of the membrane. These results indicate that activation of the GABA system is a possible mechanism of action of pyrazolopyridines. In the second part of the study binding experiments were used to provide evidence for the presynaptic localisation of GABA receptors on primary afferent terminals in the dorsal horn of the rat spinal cord. Capsaicin-induced degeneration of primary afferent fibres significantly reduced the number of GABA receptors in the dorsal spinal cord, whereas the number of benzodiazepine and glycine receptors remained unchanged. The results support the role of GABA as transmitter involved in presynaptic inhibition in the spinal cord.

Properties of [3H]taurine release from crude synaptosomal fractions of rat cerebral cortex.

The release of previously accumulated [3H]taurine and [14C]GABA from crude synaptosomal (P2) fractions isolated from rat cerebral cortex was studied using a superfusion system. The spontaneous efflux of [3H]taurine and [14C]GABA was stimulated by elevated concentrations of K+ (15--133 mM) in a concentration-dependent manner. This K+-stimulated relase of [14C]Gaba but not of [3H]taurine was enhanced in the presence of Ca2+. However, addition of 3 mM Ca2+ to the superfusion medium in the presence of the ionophore A 23187 resulted in a stimulation of the release of both [3H]taurine and [14C]GABA. These results are discussed in connection with the cellular localization of taurine in the central nervous system.

[Absence of bioavailability of HPL following intramuscular application (author's transl)]. / Fehlende Bioverfügbarkeit von HPL nach intramuskulärer Zufuhr.

Repeated intramuscular application of HPL to pregnant women did not significantly influence serum concentrations of HPL, SP-1 and estriol. Thus, this mode of application seems to be not adequately for substitutional therapy during pregnancy.