I.L. Bonta

Mianserin hydrochloride: Peripheral and central effects in relation to antagonism against 5-hydroxytryptamine and tryptamine

Abstract 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.

Mechanism of selective cardiac vagolytic action of pancuronium bromide. Specific blockade of cardiac muscarinic receptors

Abstract 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.

1-Hydroxy-3-amino-pyrrolidone-2 (HA-966): A new GABA-like compound, with potential use in extrapyramidal diseases

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 effects of mianserin hydrochloride on the vascular responses evoked by 5-hydroxytryptamine and related vasoactive substances.

Abstract 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 latters vasoconstrictor effect in the external carotid bed.

Pharmacological interaction between pancuronium bromide and anaesthetics

Abstract 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.

Haemorrhagic mechanisms of some snake venoms in relation to protection by estriol succinate of blood vessel damage

Abstract 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.

Method for study of snake venom induced hemorrhages.

Abstract 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.

Interaction between PAF-acether and drugs that stimulate cyclic AMP in guinea-pig alveolar macrophages

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.

Specific oedema-inhibiting property of a natural anti-inflammatory factor collected from inflamed tissue

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.

Different potency of pancuronium bromide on two types of skeletal muscle

Abstract 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.