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The earlier finding that γ-hydroxybutyrate and HA-966-induced depression of the central nervous system was associated with the increase of dopamine concentration and block of its release, prompted this study of the influence which the monoaminergic system may have upon the electrocorticogram in rats. The synchronization induced by α-methyl-p-tyrosine began earlier than the decrease of the duration of arousal, indicating different sensitivities to the depressive drug action of structures responsible for synchronizing and for arousal. Five mg kg HA-966 in diethyldithiocarbamate desynchronized animals increased the amplitude but the duration of arousal was unchanged. p-Chlorophenylalanine treatment of rats did not influence the synchronizing effect of HA-966 (10–20 mg kg ) or the inhibitory effect upon the duration of arousal. Haloperidol (100 μg-4 mg kg ) potentiated the synchronizing effect of y-hydroxybutyrate and HA-966. The number of phasic discharges in the electrocorticogram induced by treatment with anaesthetic doses of γ-hydroxybutyrate were increased by the low dose of haloperidol (100 μg kg ), while the higher dose (4 mg kg ) was ineffective. Animals with intact and lesioned substantia nigra compacta responded equally to the synchronizing activity of HA-966 and γ-hydroxybutyrate. Therefore, it is concluded that their effect is not due to the accumulation of dopamine in the nigrostriatal system.

dl-5E, 19,14-di dehydro-carbo-prostacyclin (DDH-carbo PGI 2 ), a stable prostacyclin (PGI 2 ) derivative, but not prostaglandin (PG) E 2 , stimulated the adenylate cyclase of synovial fluid macrophages, isolated from rheumatoid patients with an active synovitis, in a dose dependent manner (10–1000 ng/ml). DDH-carbo PGI 2 also stimulated synovial macrophage cAMP synthesis when injected into the knee joint. Exogenous arachidonic acid (AA) had little effect on cyclic-AMP (cAMP) formation or PGI 2 release (assayed as 6ketoPGF 1α ). It stimulated, however, the release of PGE 2 and, to a lesser extent, thromboxane (Tx) A 2 (measured as TxB 2 ).

The venom ‘Bothrops jararaca’ anda high molecular weight fraction obtained from it induced vasculotoxic effects when applied on the exposed surface of the lung of the dog and increased the vascular permeability when injected into the rat skin. These effects were compared to those evoked by other venoms and potential mediators. The increase in vessel permeability due to ‘B. jararaca’ venom was feebly affected by antiserotonin and antihistamine agents and was presumably due to kinin release. The effect on the lung surface was related to the coagulant and necrogenic properties of the venom and was suppressed by EDTA, promethazine and specific antiserum. A kinin releasing enzyme extracted from the venom increased the vascular permeability but had no effect on the lung. Venoms from ‘Crotalus adamanteus’ and from ‘Crotalus durissus terrificus’ also increased the vascular permeability, but were inhibited by antihistamine/antiserotonin agents; this blockade uncovered a marked skin hemorrhagic effect due to ‘Crotalus adamanteus’. Despite this activity, no vasculotoxic effect was found when ‘Crotalus adamanteus’ venom was applied to the lung. Effects of the tested venoms and enzymes are highly specific for either vascular bed, depending upon the availability on the challenged sites of different tissue components and on the specific properties of the venoms.

A23187-stimulated cytostatic activity of peritoneal macrophages towards P815 tumor cells served as a model for macrophage activation: A macrophage enriched preparation, separated on the basis of cell size in a discontinuous FCS gradient column, expressed cytostatic activity when stimulated by A23187. This was inhibited dose-dependently, by AA-861 but not by nordihydroguaiaretic acid (NDGA). AA-861 inhibited 5-lipoxygenase specifically, NDGA inhibited both 5-lipoxygenase- and cyclooxygenase activity. The ratio cyclooxygenase/lipoxygenase products increased with AA-861 but not with NDGA. These results show that lipoxygenase products are necessary for expression of cytostatic activity of these arachidonic acid metabolite-producing macrophages and that the ratio cyclooxygenase/lipoxygenase metabolites plays an important role in macrophage activation.

A method is presented which provides for a simple and rapid determination of PGE2 receptors on viable peritoneal macrophages. Incubation of the harvested cells with (3H)PGE2 revealed specific binding of (3H)PGE2 by use of the Millipore filter assay system. Maximum binding was attained in the presence of 1 mM EDTA. Specific binding was saturable at 65 fmol/mg protein with an equilibrium dissociation constant (Kd) of 3.2 X 10(-8)M. Inhibition of (3H)PGE2 binding with unlabelled prostaglandins revealed a potency series of PGE2 greater than PGE2 greater than PGI2. The PGE2 concentration which displaced 50% of the labelled ligand was 10(-7)M. Comparable kinetic data were obtained for adenylate cyclase stimulation, since the concentration which showed a halfmaximal stimulation of cAMP production was 2 X 10(-7)M of PGE2. Since PGE1 and PGI2 compete with (3H)PGE2 binding in a non-parallel manner compared to PGE2 itself, it is proposed that macrophages possess different types of PG receptors.

The interaction between the steroidal neuromuscular blocking agent pancuronium bromide and two anaesthetic agents was investigated in cats. Thiopentone or halothane reduced the effective neuromuscular blocking dose of pancuronium bromide. Under the influence of these the block anaesthetics induced by pancuronium bromide remained reversible by neostigmine. Pancuronium bromide did not influence the EEG pattern produced by thiopentone anaesthesia, nor did it enhance the blood pressure depressing effect of the barbiturate. The hypotension occurring with halothane was unchanged when pancuronium bromide was administered although occasionally the neuromuscular blocking steroid appeared to counteract the hypotensive effect of halothane to a small extent. Pancuronium bromide blocked several circulatory responses caused by peripheral vagal stimulation, but did not influence similar responses due to injected acetylcholine; nor did it markedly inhibit the contractions of the gut induced by vagal stimulation.

In heart-lung preparations of dogs, the effect of estriol-16,17-disodium succinate** was studied on circumscribed pulmonary haemorrhages induced by the local application of cobra venom on to the lung surface. Aqueous solutions of estriol-16,17-disodium succinate were either applied topically at the site of exposure to the venom, or added to the perfusing blood. Irrespective of the route of administration, estriol-16,17-disodium succinate delayed the appearance and diminished the intensity of the haemorrhages. The weak estrogenic activity of estriol-16,17-disodium succinate, the use of an isolated organ system and the rapidity with which it develops all suggest that the antihaemorrhagic effect and the conventional estrogenic effects occur independently. The use of heparinized dogs and defibrinated blood both favour the view that the antihaemorrhagic effect observed was of vascular origin. Some possibilities regarding more detailed aspects of the mechanism of this effect are discussed.

α- and β-adrenergic blockers have been examined on the bradykinin- and adrenaline-induced relaxation of the acetylcholamine contracted guinea-pig ileum. The α-adrenergic blocker piperoxan potentiated, while phentolamine reduced the bradykinin relaxation. Both reduced the acetylcholamine contraction, but had no effect on the adrenaline relaxation. The bradykinin relaxation of the guinea-pig ileum was about 10 times more sensitive to phentolamine than the rat duodenum. The β-adrenergic blocker propranolol potentiated the bradykinin relaxation and reduced the acetylcholine contraction. Sotalol was in these respects less potent than propranolol. The adrenaline relaxation was partially blocked by propranolol, but almost completely by satalol. A combination of phentolamine and propranolol slightly potentiated the bradykinin relaxation, and partially blocked the adrenaline relaxation. The bradykinin relaxation is not due to a direct action on either the α- and β-adrenergic receptors of the guinea-pig ileum. The potentiation of the 0radykinin relaxation is probably indirect via the reduction of the acetylcholine contraction. The action of phentolamine cannot be explained by this mechanism. Seemingly only β-adrenergic receptor activity mediates relaxation with adrenaline.

The selective vagolytic action of the potent steroidal neuromuscular blocker, pancuronium on the heart was analysed in cats, dogs and in isolated tissues of guinea-pigs. The compound not only suppressed the inhibitory effects of vagal stimulation, but also selectively antagonised the negative inotropic and chronotropic actions of parasympathomimetic compounds without appreciably modifying their vascular effects or the responses to potassium chloride. Antagonism of the above compounds was competitive and was more selective on spontaneously beating auricles than on the ileum when compared with atropine. Thus, pancuronium possessed a more specific blocking action on the muscarinic receptors of the heart. These receptors, in analogy with the cardiac beta adrenergic receptors, may be different from muscarinic receptors present elsewhere. Study of the cardiovascular actions of pancuronium in dogs indicated that the compound was well tolerated even in relatively high doses. This lack of adverse cardiovascular effects has already been demonstrated in several clinical reports.

The duration of electrically evoked hippocampal afterdischarges was studied in conscious rabbits which were subjected to acute treatment with drugs known to affect noradrenaline stores of the brain. Within two hours of the intravenous administration of high doses of reserpine, the hippocampal afterdischarges were markedly prolonged. a -methyl-dopa had no effect on the normal duration of the hippocampal afterdischarges, but it completely prevented the prolongation due to acute reserpine treatment.

The inhibition of the collagen-induced platelet aggregation by PGE1 is considerably reduced in the plasma of EFA-deficient rats.

International audience; The PAF-acether (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine)-induced arachidonate release from alveolar macrophages was significantly reduced by prostaglandin E2 (PGE2) and by the beta-adrenoceptor agonist salbutamol. In addition, PAF-acether markedly reduced the increase in intracellular cyclic AMP (cAMP) concentrations induced by PGE2 and salbutamol. Our data indicate an inverse relationship between intracellular cAMP levels and free arachidonate availability in alveolar macrophages treated with PAF-acether. A rise in intracellular cAMP therefore represents an important alternative route for controlling the effects of PAF-acether and the resulting inflammatory alterations in the respiratory system.

Summary 1 The drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of GABA, has been studied for neuro-pharmacological properties and for effects on the catecholamine content of the corpus striatum. 2 The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA-966 caused periodical sleeping episodes. 3 The exploratory behaviour and the amphetamine-induced motor activity in mice were blocked by HA-966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA-966 differs from neuroleptics. 4 Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA-966. The muscarinic effects of tremorine were not reduced by HA-966, indicating a selective central antitremor effect. 5 HA-966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA-966 depresses central internuncial neurones. 6 In rats and rabbits HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between ‘sleep-EEG’ and behaviour. 7 In rat brain, HA-966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5-hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with α-methyl-p-tyrosine. 8 Several effects of intravenously administered HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA-966 is converted to a pharmacologically active metabolite. 9 The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA-related hypothesis as to the mode of action of HA-966 is presented.

The isolated guinea-pig ileum, challenged by agonist, was used to study the effect of bradykinin. In the presence of acetylcholine producing approximately 60% of maximum contraction, bradykinin caused relaxation followed by contraction. The biphasic response to bradykinin was also found in the presence of histamine, eledoisin, angiotensin, prostaglandin F2α and transmural electrical stimulation. The conditions for bradykinin-induced relaxation were not found after treatment by bradykinin, and potassium or barium chloride. Under conditions where bradykinin produced a biphasic response, acetylcholine, histamine, eledoisin, angiotensin, prostaglandin F2α and lysine-vasopressin only contracted the ileum, while adrenaline, noradrenaline, oxytocin, calcium and magnesium chloride only relaxed. On increasing the percentage of maximum contraction with acetylcholine, an inverse relationship with relaxation by bradykinin was found. Tachyphylaxis was not present with the bradykinin-induced relaxation. The relaxing effect of bradykinin is more likely to be due to a direct action on the muscle cell membrane than to a release of a mediator or to blockade of a receptor mediating contraction.

On the basis of previous findings it was suggested that estriol-16,17-dihemisuccinate might counteract the development of induced local oedemas. To test this assumption, a study was performed using the rat paw oedema test. Depending on the material used, three types of oedema could be produced: Rapid and transient type, when serotonin, histamine, compound 48/80, chicken egg white and polyvinylpyrrolidone were the inducers. Slow and long lasting type, with kaolin as inducer. Rapid and long lasting type when cobra venom served as inducer. Cyproheptadine inhibited the rapid and transient type of oedema, except when polyvinylpyrrolidone was used. Furthermore cyproheptadine counteracted the rapid phase of the oedema produced by cobro venom, but did not influence the slow and long lasting oedema induced by kaolin or the delayed phase of the cobra venom oedema. Phenylbutazone counteracted the slow and long lasting swelling induced by kaolin and the delayed phase of swelling induced by the snake venom, but exerted no effect on any rapid and transient oedema, or on the early phase of oedema produced by snake venom. Estriol-16,17-dihemisuccinate did not selectively inhibit any one kind of oedema more than another, but counteracted at approximately equal potency all the types of oedema studied.

The hemorrhagic factors from the venoms of Naja naja, Agkistrodon piscivorus and Apis mellifera have been fractionated on Sephadex G 50. Different polypeptides with a molecular weight of less than 10·000 are responsible for the hemorrhagic activity. The hemorrhagic effect observed on canine lung surface caused by bee venom cannot be attributed to phospholipase A activity. Although the snake venom fractions which induced hemorrhages possessed phospholipase A activity, it appears that the enzyme is not responsible for the hemorrhages. Heparin was found to form an inactive complex with the hemorrhagic factors of Naja naja and bee venom, whereas the hemorrhagic activity of Agkistrodon piscivorus venom was unaffected by heparin. Protamine could release the hemorrhagic factor in an active form, from the inactive complexes. Esterase activity of Agkistrodon piscivorus venom and Bothrops jararaca can be inhibited by Trasylol (R).

Eine hochmolekulare Verbindung wurde aus Exudaten von Granulombeuteln von Ratten gereinigt. Diese Substanz, i.p. an Ratten verabreicht, hemmt das durch Kaolin oder durch Carrageenin erzeugte Pfotenoedem, nicht dagegen das durch Histamin, Serotonin oder Polyvinylpyrrolidon erzeugte Oedem.

The vascular haemorrhagic action of cobra venom depends on the presence of a heparin precipitable material, the latter being possibly the so called Direct Lytic Factor, which apparently renders the phospholipase of the venom capable of causing bleeding. The haemorrhagic action of Agkistrodon piscivorus venom is independent of a heparin precipitable factor and it is also unlikely that the phospholipase activity of the venom is responsible for the haemorrhages. Estriol succinate counteracts the bleedings caused by cobra venom, but not the haemorrhages produced by the snake venom lacking the heparin precipitable factor.

Mianserin hydrochloride, a new anti-5-hydroxytryptamine agent, was compared with cyproheptadine with respect to a variety of responses evoked by 5-hydroxytryptamine and other agonists. Central effects against tryptamine responses and general depressant effect on CNS were also studied. The two antagonists induced comparable inhibition against responses in which D-receptors of 5-HT were involved. Mianserin displayed α-adrenolytic activity and did not antagonize muscarinic effects of acetylcholine; the opposite was true for cyproheptadine. Mianserin was more effective than cyproheptadine in counteracting tryptamine-induced responses in rabbits and rats. Cyproheptadine produced diffuse depression of the CNS, with marked elevation of the threshold to electric stimulation of the brain stem reticular system in rabbits, persistent block of the acoustic arousal in rats and rabbits and prolongation of barbiturate sleep in rats. Mianserin however did not produce CNS depression, other than transient inhibition of the sensory activation of the EEG in rabbits. The earlier postulated structure-activity relationship between mianserin and cyproheptadine does not appear to apply to effects other than certain 5-HT responses and central tryptamine effects.

The damaging effect of cobra venom on the pulmonary microcirculation was studied. Also studied were the inactivation of the venoms vasculotoxin by heparin and the protective effect of heparin on the vessels. Mice injected intrathoracally with the venom of Naja naja (Indian cobra) developed diffusely hemorrhagic lungs; lung weight was increased as a consequence of local blood extravasation. In vitro addition of heparin to Naja naja venom abolished the hemorrhage, prolonged survival, but did not prevent death. This supports the view that the heparin-precipitable strongly basic vasculotoxic factor of the venom is not identical with the main lethal (neurotoxic) component. Heparin in vivo also prevented pulmonary hemorrhage and prolonged survival when administered locally several hours prior to the venom injection. Arguments are presented to show that the protective effect of heparin administered in vivo is a possible reflection of its action on the capillaries or the pericapillary connective tissue, resulting in an increased resistance of the vessels towards damage.

A method to study the vascular hemorrhagic effects of snake venoms is described. It consists of topical application of the venoms to the lung surface in dog open-chest preparations and allows qualitative and quantitative assessment of the hemorrhages. The venoms of Naja naja and Naja nigricollis produced diffuse bleedings, while hemorrhages caused by the venom of Agkistrodon piscivorus had a petechial character. A. piscivorus venom displayed two to three times the potency of N. naja venom with regard to onset and intensity of the hemorrhages. Both venoms contain heparin precipitable materials. Addition of heparin to the Naja venoms abolished their hemorrhagic activity, while the A. piscivorus venom retained the hemorrhagic effect. A possible relationship between the hemorrhagic effects and some enzymatic activities of the venoms is discussed. There was no correlation between hemorrhagic and BAEE-esterasic activity of the venoms. It is unlikely that phospholipase-A alone plays a role in the hemorrhagic effect.

The effect of the competitive neuromuscular blocking steroid pancuronium bromidee (2β, 16β-dipiperidino -5a-androstane-3a, 17β-diol diacetate dimethobromide) was studied on tetanic contractions of two kinds of muscle in the cat. The compound was slightly more potent in producing block on the tibialis, a white muscle, than on the soleus, a red muscle. Pancuronium bromide is different in this respect from the prototype competitive blocker d-tubocurarine. With succinylcholine the preference for blocking the tibialis rather than the soleus is more pronounced than with pancuronium bromide; the latter thus occupies in this respect an intermediate position between the other two drugs. The magnitude of respiratory depression produced by pancuronium bromide also seems to indicate its intermediate character concerning muscle selectivity. Neostigmine reverses promptly and completely the block produced by pancuronium bromide on the tibialis, confirming that its mode of action is non-depolarizing, although its muscle selectivity is unusual for this type of drug. The blood pressure remained steady or increased slightly after pancuronium, whereas hypotension developed after tubocurarine.

Among a few newly synthesized novel substituted piperazine derivatives, 2-methyl-1,2,3,4,10,14b-hexahydro-2H-pyrazino (1,2-f) morphanthridine hydrochloride (mianserin hydrochloride) was found to be a potent antagonist of some actions of 5-hydroxytryptamine (5-HT) and histamine. The present experiments were designed to study the effect of mianserin on some cardiovascular parameters in dogs and on the vascular responses of some physiologically occuring substances. Mainserin effectively antagonized the hypertensive, coronary vasodilator and venoconstrictor actions of 5-HT. In addition, the hypotensive action of histamine and the hypertensive action of catecholamines in dogs were partially antagonised by mianserin. Antagonism of noradrenaline-induced vasoconstriction was confirmed in the perfused central artery of the rabbit ear. However, in contrast to the above-mentioned anti 5-HT actions, mianserin enhanced the vasoconstrictor response to 5-HT in the external carotid bed of dogs indicating that the receptors for 5-HT in the carotid bed differ from those present in other vascular and non-vascular smooth muscles. It is argued that the possible effectiveness of such drugs in migraine may not be due to antagonism of the actions of 5-HT, but could possibly result from a potentiation of the latter's vasoconstrictor effect in the external carotid bed.

Hemorrhagic snake venoms contain a multitude of factors which either through a direct action or indirectly through the release of some mediator disturb the integrity of the vessel wall. For example the protease and/or esterase components in some of such venoms are enzymes known to release polypeptide kinins, which are considered as one of the mediators of microvascular functional disturbances. Previously we developed a method (4,5), which allows to study quantitatively the hemorrhagic effect of snake venoms on pulmonary surface vessels. The venom of Agkistrodon piscivorus is recognized to contain a kinin releasing component (10). We therefore examined the hemorrhagic action of this venom under the influence of some compounds which interfere with the kallikrein-kinin system. The effect of the same compounds were also studied on the hemorrhagic action of Naja naja venom, which is not known to release kinins and from which we have shown that its hemorrhagic effect is dependent on its content of a basic polypeptide (5), the latter unlikely to possess protease or esterase activity (6).

Carrageenin has kininogen depleting properties in the rat (1). Its local oedema inducing effects are inhibited by phenylbutazone and other non-steroidal antiinflammatory drugs. The kaolin induced elevation of kinin activity in the rat oedema fluid is also counteracted by phenylbutazone, while this drug is unable to inhibit the polyvinylpyrrolidone induced oedema, where a lack of increased kinin activity was demonstrated (2). In the present work additional support is given to the postulation that the antiinflammatory action of phenylbutazone may partly be due to its interference with the kallikrein-kinin system.