Failure of (+)-naloxone to accelerate feline colonic transit

To determine whether the colonic transit accelerating effect of (-)-naloxone (0.3 mg/kg, i.m.) is due to an action at opioid receptors or a direct pharmacologic effect, its enantiomer, (+)-naloxone (0.3 mg/kg, i.m.), was administered to cats and compared to saline control using colonic transit scintigraphy. Transit was not accelerated by (+)-naloxone. The effects of naloxone on colonic transit are thus stereospecific, and are probably mediated by opioid receptors.     

Modification of the effect of cardio-accelerator nerve stimulation in dogs by clonidine and several alpha-adrenolytics]

In dogs anaesthetized with pentobarbital (30 mg. kg -1 i.v.), clonidine (0,01 mg.kg-1 i.v.) reduced the tachycardia induced at low frequencies by stimulation of the cardiac nerve. The effects of some alpha-adrenoceptor blocking agents on this effect have been studied. Small doses of yohimbine (0.3 mg. kg-1 i.v.) or piperoxan (0.3 mg. kg-1 i.v.) increased the effects of the stimulation and in addition antagonized the inhibitory effects of clonidine and reversed the pressor response to adrenaline. Thymoxamine (1 mg.kg-1 i.v.) and prazosin (1 mg.kg-1 i.v.) did not increase the effect of the stimulation of the cardiac nerve, but reduced the effect of clonidine. ARC239 (0.05 mg.kg-1) reversed the pressor response to adrenaline but even at high doses did not increase the effects of the stimulation of the cardiac nerve or the effects of clonidine. These observations afford further evidence for a dissimilarity between pre and post-synaptic alpha-adrenoceptors.     

Influence of flupirtine,a novel nonopioid analgesic agent on somatosensory evoked potentials in rats

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID₅₀-values of 5.4 mg/kg (2.6–9.3 mg/kg) and 7.9 mg/kg (3.9–13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Action of N-butylnorsympathone on the effects of cardioaccelerator nerve stimulation in the dog]

In Dogs anaesthetized with pentobarbital (30 mg . kg-1), N-butylnorsympathone (20 mg . kg-1 i.v.) reduced the bradycardia induced by stimulating the cardiac nerve (1, 2, 5, 10 Hz). Phentolamine (1 mg . kg-1 i.v.) or yohimbine (0.3 mg . kg-1 i.v.), two potent alpha-adrenoceptor blocking agents known to block presynaptic alpha-adrenoceptor induced a recovery of the effect of cardiac nerve stimulation. Prazosine (0.050 mg . kg-1 i.v.) an alpha-adrenoceptor blocking agent known to be ineffective on presynaptic alpha-adrenoceptors did not induce a recovery. However neither phentolamine or yohimbine were able to prevent the effects of N-butylnorsympathone. Neither haloperidol (0.050 to 2 mg . kg-1 i.v.) or pimozide (0.20 to 1 mg . kg-1 i.v.) induced a recovery or prevented the effects of N-butylnorsympathone. These results suggest that N-butylnorsympathone may stimulate presynaptic receptors which do not resemble classical presynaptic alpha-adrenoceptors or dopamine receptors.     

Blockade of GABAB receptors accelerates amygdala kindling development

The aim of this study was to investigate the putative role of GABA_B receptors in the development of amygdala kindling in rats. The effects of the GABA_B blocker CGP 35348 and the GABA_B agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1–5 classified by Racine) and duration of afterdischarges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p, which blocks central GABA_B receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABA_B receptors and thereby exerted a depressant effect on kindling development.     

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Blockade of GABAB receptors accelerates amygdala kindling development.

The aim of this study was to investigate the putative role of GABAB receptors in the development of amygdala kindling in rats. The effects of the GABAB blocker CGP 35348 and the GABAB agonist baclofen on the progressive development of behavioural seizure symptoms (stages 1-5 classified by Racine) and duration of after-discharges (AD) were studied. CGP 35348 at a dose of 300 mg/kg i.p., which blocks central GABAB receptors, moderately but consistently accelerated the development of behavioural seizure symptoms. CGP 35348 had no marked effect on the duration of ADs corresponding to the different seizure stages. L-baclofen (6 mg/kg i.p.) had a dual effect on kindling development. It retarded the development of the behavioural symptoms, but increased the duration of AD. In conclusion, the results suggest that synaptically-released GABA activated GABAB receptors and thereby exerted a depressant effect on kindling development.     

The effects of physostigmine on the oxygen uptake in rat brain tissue

Summary Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.This work was supported by a grant from Serbian Republic Scientific Fund (ZMNU SR Srbija), Belgrade (Yugoslavia).The authors wish to acknowledge the skilful technical assistance of Lj. Krsti.     

Baclofen prevents rapid amygdala kindling in adult rats

This study investigates the effect of the gamma-aminobutyric acid (GABA_B) agonist, baclofen, on amygdala kindling in adult rats. Baclofen has been reported to be anticonvulsant in a variety of seizure models and prevents kindling in immature rats. These experiments describe the effects of baclofen (2, 5 and 10 mg/kg, i.p.) on the afterdischarge threshold and kindling rate. Baclofen, 10 mg/kg, significantly increased the afterdischarge threshold in the amygdala. Baclofen at 5 and 10 mg/kg, retarded the rate of kindling as measured by the number of stimuli required to advance to subsequent seizure stages. These results suggest that baclofen may decrease the local excitability of the amygdala and retard the rate of seizure spread (or generalization) throughout the brain. Baclofen, acting at GABA_B receptors exerts an anticonvulsant effect on amygdala kindling in these experiments.     

The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP+-lesioned mice

Orally administered Madopar (levodopa/benserazide 41) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP⁺-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.     

The effects of physostigmine on the oxygen uptake in rat brain tissue.

Physostigmine in a dose of 0.1 mg/kg i.v. expressly stimulated the oxygen uptake in the rat cerebral cortex. This effect was blocked by propranolol and seems be mediated by catecholamines. Since atropine also antagonized the stimulant effect of physostigmine, it appears that the action of physostigmine is primarily cholinergic and that the adrenergic effect is a secondary phenomenon. The higher dose of physostigmine (0.4 mg/kg i.v.) caused a depression of rat brain oxygen uptake.     

Prostaglandin-induced serotonin release

Zusammenfassung Bei Ratten wurde die Gesamtmenge von Serotonin in der Fundus- und Atriumschleimhaut sowie im mittleren Jejunum bestimmt. Prostaglandin E₁ (200 g/kg, s.c. oder i.v.) reduzierte den Serotoninspiegel weder in den Kontrolltieren noch in mitp-Chlorophenylalanin (150 oder 300 mg/kg) oder mit Reserpin (5 mg/kg) vorbehandelten Tieren.     

Stimulierung der Atmung durch Bradykinin und Kallidin

Summary In guinea pigs and rabbits small doses of bradykinin and kallidin (1–8 µg/kg i.v.), which have no bronchoconstrictor effect, stimulate respiration causing tachy- and hyperpnea. Bilateral vagotomy as well as salicylates (4–40 mg/kg i.v.) abolish these respiratory responses.     

Reduction of hypoxia-induced disturbances by previous treatment with benserazide and L-dopa in rats.

Pretreatment by benserazide (50 mg/kg i.p.) and L-Dopa (100 mg/kg i.p.) in rats induces a reduction of the diminution of motility after hypoxia and a stabilization of cerebral blood flow during and after hypoxia. An overload of cerebral dopamine and norepinephrine seems to be the original process of this phenomenon.     

Inhibition of saline-induced diuresis in the rat by sulpiride.

Sulpiride (120 mg/kg, i.p.) inhibited saline-induced diuresis in the rat, an effect not observed with haloperidol, clozapine, pimozide or chloromazine. The antidiuretic effect of sulpiride also occurred in hypophysectomized rats suggesting that the response was not prolactin-mediated.     

Inhibition of saline-induced diuresis in the rat by sulpiride

Summary Sulpiride (120 mg/kg, i.p.) inhibited saline-induced diuresis in the rat, an effect not observed with haloperidol, clozapine, pimozide or chlorpromazine. The antidiuretic effect of sulpiride also occurred in hypophysectomized rats suggesting that the response was not prolactin-mediated.     

Leishmania donovani in hamsters: Stimulation of non-specific resistance by novel lipopeptides and their effect in antileishmanial therapy

Several novel type of lipopeptides were synthesized and evaluated for their ability to stimulate non-specific resistance againstLeishmania donovani infection. Peritoneal macrophages isolated from young male hamsters treated with muramyl dipeptide (MDP) and various synthetic lipopeptides (6 mg/kg i.p.) 7 days earlier, were cultured in vitro and challenged 24 h later withL. donovani promastigotes. One lipopeptide, Central Drug Research Institute (CDRI) compound 86/450, exhibited significantly higher immunostimulatory activity than MDP. Its prophylactic activity was further confirmed in hamsters by giving 2 split doses of 3 mg/kg of the compound spaced at 2 weeks, i.e. on day –7 and +7 of challenge withL. donovani amastigotes. The prophylactic effect lasted for 7 days following the last treatment with compound 86/450. The antileishmanial action of sodium stibogluconate (SAG) was also found to be enhanced by 16% in hamsters primed with compound 86/450.CDRI Communication No. 5034.     

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.C1) in rats.

The biological half-life of 2-PAM.C1 was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.     

Beeinflussung des Generationszyklus und seiner Teilphasen bei Ehrlich-Aszitestumoren verschiedener Ploidie durch Cyclophosphamid

Summary The effect of the alkylizing agent cyclophosphamide (100 mg/kg i.p.) on the cell cycle of the diploid (EAT dipl.) and hypertetraploid (ELT) Ehrlich ascites tumor growing in the peritoneal cavity of male NMRI-mice has been studied by autoradiography with H³- and C¹⁴-thymidine (double labelling technique and method of labelled mitoses). The results suggest that the proliferation kinetics of tumor cells after administration of cyclophosphamide is dependent essentially on the type of tumor strain tested.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a¹⁴CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p<0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.