Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils.

The neurokinin (NK) substance P (SP), which is a mediator of neurogenic inflammation, has been reported to prime human polymorphonuclear neutrophils (PMNs). The priming effects of SP on PMNs activated by recombinant interleukin-8 (rIL-8) were investigated. SP enhanced, in a dose- and time-dependent way, the rise in cytosolic free-calcium concentration, [Ca(2+)]i, evoked by the chemokine. The priming effects of SP were abolished by exposing PMNs to a calcium-free medium supplemented with EGTA. The C-terminal peptides SP(4-11) and SP(6-11) but not the N-terminal peptide SP(1-7) shared the priming effects of SP. The selective NK-1 receptor agonist [Sar-9, MetO2-11]SP mimicked the effects of SP, which were not reproduced by the selective NK-2 receptor agonist [betaAla-8]-NKA(4-10) or the selective NK-3 agonist senktide. Two selective NK-1 antagonists, CP96,345 and L703,606, dose dependently inhibited SP priming effects. These results demonstrated that SP primes PMNs exposed to rIL-8 and suggested that SP priming effects are receptor mediated.

Studies on the in vitro inversion of flurbiprofen.

This paper reports in vitro studies on the metabolic inversion of flurbiprofen (FL), an arylpropionic acid antiinflammatory agent (2-APA). The inversion was studied with both rac-FL and R-FL, by incubation with rat hepatic microsomes, in the presence of either CoASH and ATP or NADPH. The two isomers of the drug were separated as their (+)-(R)-1-phenylethylamides by direct phase high-performance liquid chromatography on a silica gel column with an achiral mobile phase. The inversion was more pronounced in the presence of CoASH and ATP for both the racemate and the R-isomer, which supports the key role of CoA thioesters in the metabolic inversion of profens. The inversion observed in the presence of NADPH suggests that, when the incubation is run with hepatic microsomes, a CYP450-mediated pathway is also active. In order to get more insight into the CYP450-mediated inversion pathway, we studied the effect of irradiating microsomes with a low dose of He-Ne laser radiation (0.2 J). Such irradiation caused a significant increase in inversion at all times studied and normalized the anomalous value of inversion observed at 15 min in this pathway.

Effect of in vivo He-Ne laser irradiation on biogenic amine levels in rat brain.

In order to elucidate the metabolic modifications induced in rat brain by low power He-Ne laser irradiation in vivo, the variations in the biogenic amine levels in cortex, striatum and hippocampus were studied. Noradrenaline (NA), dopamine (DA) and serotonin (5-HT) were evaluated by HPLC-EC on irradiated rats, untreated rats (controls) and rats which had undergone restraint stress (stressed). The results obtained on groups of four to eight rats assayed individually showed that irradiation caused a strong increase in 5-HT in striatum and hippocampus, a small but significant decrease in NA in cortex, and DA levels were not significantly affected. Restraint stress per se led to a considerable decrease in 5-HT and DA in striatum and hippocampus, but did not significantly alter the NA levels.

Rat brain metabolism enzyme activity variations following He-Ne laser irradiation.

In order to gain insight into the metabolic modifications induced in rat brain tissues by helium-neon (He-Ne) laser irradiation, in the research described here, we investigated the variations in the activity of the enzymes aspartate transferase (AST, EC 2.6.1.4), both cytosolic and mitochondrial, glutamate dehydrogenase (GIDH, EC 1.4.1.3), and total superoxide dismutase (SOD, EC 1.15.1.1), in the brain of rats treated with a very small dose (1.08 J) of He-Ne laser radiation. The rats were sacrificed 4 h after the treatment. The enzymes were evaluated spectrophotometrically in brain extracts of irradiated animals and also in untreated rats (controls) and rats that underwent simulated treatment (stressed). The data obtained from 5-10 animals assayed individually showed that, in the in toto brain tissues of the irradiated rats compared to the stressed rats, there was a marked increase of total SOD, together with an appreciable decrease of cytosolic AST, and insignificant variations in mitochondrial AST and GIDH. Stress alone caused a considerable decrease of total SOD and small but statistically significant increases of s-AST, m-AST, and GIDH.

Effects of combinations of arecoline and atropine on mouse motor activity.

1. Effects on motor activity were studied after acute administration of arecoline, atropine alone and in combination in the mouse. 2. Atropine from 15 to 45 mg/kg increased motor activity. 3. A reduction in activity was observed at doses of arecoline above 0.2 mg/kg. 4. An antagonism between arecoline and atropine was observed only at low doses of arecoline, while higher doses of arecoline in association with atropine increased activity.

Action of a chronic arecoline administration on mouse motility and on acetylcholine concentrations in the CNS.

The modifications of mouse motility and of the levels of acetylcholine (ACh) in two sections of the CNS caused by a chronic administration of 4.5; 9.5; 28.5 and 60 mg kg-1 day-1 of arecoline for 20 days have been studied. At low doses (4.5 and 9.5 mg kg-1 day-1), arecoline caused no modification of the ACh levels and of the motility. The higher doses (28.5 and 60 mg kg-1 day-1) caused a reduction of the mouse motility and an increase of the ACh levels in the subcortical structures of the CNS of the mouse.

Action of arecoline on the levels of acetylcholine, norepinephrine and dopamine in the mouse central nervous system.

Modifications caused by arecoline (2 mg/kg and 10 mg/kg injected subcutaneously) in the levels of acetylcholine (ACh), norepinephrine (NE) and dopamine (DA) in the mouse cortex and "subcortex" were studied. The animals were killed by microwave irradiation of the head 15 minutes after drug administration. Arecoline 10 mg/kg caused a reduction in levels of ACh in the cortex and "subcortex" at the limit of statistical significance (p 5-10%) and a statistically significant reduction in levels on NE. A statistically significant increase in DA was observed only in the cortex after 2 mg/kg and 10 mg/kg of arecoline.

Action of a chronic administration of mescaline in dynamic behavioural situations.

The modifications of the rat behaviour caused by a chronic administration of mescaline were studied in two schedules of operant conditioning. In the "periodic conditioning" test, the schedule of reinforcement was changed from a fixed ratio to a fixed interval schedule. Mescaline (4 mg/kg/day and 10 mg/kg/day) caused no modification of the ability of the rat to adapt its behaviour to the new experimental situation. In the "reversal test" the contingency for food delivery was switched from one lever, where responses were previously reinforced to the other lever where responses had no programmed consequences. A chronic administration of mescaline (4 mg/kg/day) caused a total incapacity of the rat to switch to the lever which became reinforced in the reversal trial. A chronic administration of 9 mg/kg/day of mescaline had an excitatory effect and the number of reinforced responses in the II and III reversals exceeded the unreinforced responses in a measure greater than in the controls.

Action of hypo- and hyperthyroidism on the postmortal decay of acetylcholine in the rat spinal cord.

The postmortal decay of acetylcholine (Ach) was studied in the cervical spinal cords of rats in conditions of hyper- and hypothyroidism. The modifications of thyroid function were achieved either by chronic (20-25 days) administration of l-thyroxine or of methimazole. The basal metabolic rate and plasma T4 concentration were measured to estimate the degree of modification of thyroid activity. The levels of Ach at the start of postmortal decay were evaluated by extrapolation to time 0 of the curves of the postmortal decay of Ach and the levels of Ach at stabilization were estimated from the means of all the measures made at lapses of time over 100-200 s from death. In low and high hypothyroidism a reduction (53 and 72%, respectively) of the levels of Ach was found. A similar effect was found in hyperthyroidism: a 73 and 63% reduction of Ach levels in high and low hyperthyroidism, respectively. The level of Ach at stabilization of the postmortal decay increased only in hyperthyroid rats. The process by which Ach is destroyed is not modified in hyper- or hypothyroidism.

Mescaline action on "memory decay" and "problem solving" behavior in the rat.

The modifications of behavior caused in the rat by a chronic oral administration of mescaline have been studied in three experimental situations. In the staircase maze mescaline accelerated the spontaneous decay on the conditioned reflex (memory decay) during the period without daily training. Only the results observed at 30 mg/kg/day of mescaline were statistically significant. In a T maze two lateral alleys closed by two swinging doors, 30 mg/kg/day of mescaline increased the time spent in opening the first door. When the two doors of the lateral alleys were closed with a latch, mescaline 30 mg/kg/day, caused an increase in the time spent by the rat in opening the doors. Mescaline caused an increase in food consumption. The increase at 30 mg/kg/day is statistically significant.

The transition from a fixed ratio to a fixed interval schedule of reinforcement in hypo and hyperthyroid rats.

The modification of behavior caused by hypo and hyperthyroidism were studied when the schedule of reinforcement was changed from a fixed ratio to a fixed interval. The conditions of hypo and hyperthyroidism were obtained with a chronic administration of methimazole and of 1-thyroxine. The level of the modifications of thyroid activity was determined by evaluation of the basal metabolic rate and of the plasma levels of T4. Hyperthyroidism caused no modification of the rat behaviour. A difficulty in adapting to the new experimental situation (learning) was found in hypothyroidism. This effect is evident in high hypothyroidism. In low hypothyroidism a depression of the rat behaviour may interfere with the modification of the learning process.

Behavioral interferences modify the acceleration in memory decay caused by diazepam.

A staircase maze has been used to test the modification induced by a chronic administration of different doses of diazepam in the decay of the rat performance caused by an interruption of 20 days in the daily training. The possibility that behavioral interferences modify the diazepam effect has been examined by testing the rat in an open field or in a Y maze during the interruption of the training in the staircase maze. The diazepam effect on the rat behavior in the staircase maze increased linearly with the doses; an intercalated training in the open field increased the diazepam effect, while an intercalated training in a Y maze completely abolished the increase of forgetting caused by diazepam.

Action of antidepressants, stimulants and depressants in the transition from a fixed ratio to a fixed interval schedule of reinforcement.

1. The modifications of rat behaviour caused by imipramine, amitriptyline, doxepin, amphetamine, chlorpromazine, caffeine and diazepam were studied. 2. The schedule of reinforcement was changed from a fixed ratio to a fixed interval schedule. 3. All the studied drugs caused a depression of the rat behaviour but only tricyclic antidepressants and caffeine caused virtually no damage to the ability of the animal to adapt its behaviour to the new experimental situation.

[Electrocardiographic changes induced by various analogs of radicinin]. / Modificazioni elettrocardiografiche indotte da alcuni analoghi della radicinina.

The action of some radicinin analogues has been studied on the ECG in the rat. The most active compound is 2,3-dihydro-2, 7-dimethyl-4H,5H-pyrano [4,3-b]pyran-4,5-dione (II) which induced a significant increase of the heart rate (HR) and an evident prolongation of the PR interval, especially at the highest dose. A slight but lasting increase in HR is caused by compound (VII),3-hexanoyl-4-hydroxy-6-methyl-2H-pyran-2-one, while the compound (III), 7,8-dihydro-2,7-dimethyl-4H,5H-pyrano-[4,3-b]pyran-4,5-dione caused a small prolongation of the PR time. No significant modifications are caused by the other five compounds tested.

[Effects of various radicinin analogs on pulse amplitude and arterial blood pressure]. / Azione di alcuni analoghi della radicinina sull'ampiezza del polso e sulla pressione arteriosa.

The action of some radicinin analogues on the pulse amplitude in urethane anesthetized rats has been studied. The compounds used are:2,7-dimethyl-4H,5H-pyrano[4,3-b]pyran-4,5-dione (I); 2,3-dihydro-2,7-dimethyl-4H,5H-pyrano[4,3-b]pyran-4,5-dione (II) 7,8-dihydro-2,7-dimethyl-4H,5H-pyrano[4,3-b]pyran-4,5-dione (III) 2,3,7,8-tetrahydro-2,7-dimethyl-4H,5H-pyrano[4,3-b]pyran-4,5-dione(IV); 2,3,7,8,4',8'-hexahydro-2,7-dimethyl-4H,5H-pyrano[4, 3-b]pyran-4,5-dione (V); 3-crotonyl-4-hydroxy-6-methyl-2H-pyran-2-one (VI); 3-hexanoyl-4-hydroxy-6-methyl-2H-pyran-2-one (VII); 3-hexanoyl-5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one (VIII). A clear increase in the pulse has been seen with the compounds (II), (V) and (VII) especially at the lowest doses, while a decrease in the pulse is caused by the compounds (I) and (VIII). The studied substances have no effects on systolic blood pressure in normotensive unanesthetized rats.

[Action of salicylates on the disappearance of bacteria (Lactobacillus casei) phagocytized by polymorphonuclear cells]. / Azione di salicilati sulla scomparsa di batteri (Lactobacillus casei) fagocitati da polimorfonucleati.

This is a study of the modifications caused by acetylsalicylic acid and CuII (aspirinate)4 in the speed with which phagocytized bacteria disappear from polymorphonuclears (PMN) of the peritoneal exudate of guinea pigs. Acetylsalicylic acid inhibits the normal processes that cause the disappearance of the phagocytized bacteria; CuII (aspirinate)4, on the contrary, at low concentration (5 10(-6)) and during the first 45 minutes, causes an evident increase in the speed of disappearance of bacteria from PMN.

The associations acetylcholine-eserine and acetylcholine-morphine studied on the frog rectus abdominis muscle.

The interaction of morphine and eserine with acetylcholine (Ach) on frog rectus abdominis muscle was studied. Both eserine and morphine potentiate the effects of exogenous Ach and this effect is certainly not due to the anticholinesterase action of the two drugs. Morphine is less effective than eserine in potentiating the response of the muscle to the Ach introduced in the organ-bath. The synergisms Ach-eserine and Ach-morphine are synergisms with potentiation: it is concluded that eserine and morphine in amphibian muscle interact with specific receptors. These binding sites are different from both the esterase and the ACh binding sites of the cholinergic receptor but appear to influence its function.

Modification of the synergism acetylcholine-eserine induced by morphine in amphibian muscle.

The modification of the synergism acetylcholine-eserine induced by two different concentrations of morphine (0.2 and 8 microgram/ml) was studied on the frog rectus abdominis muscle. Morphine increases the Ach-potentiating action of low concentrations of eserine (from 3 to 40 ng/ml). On the contrary at higher eserine concentrations (from 0.1 to 1.0 microgram/ml), morphine reduces the potentiation of Ach effects caused by eserine. It is concluded that in amphibian muscle eserine and morphine potentiate the effects of exogenous Ach by acting on the same population of receptors.