链霉素降压机制的进一步研究

给乌拉坦麻醉家兔,静脉注射新斯的明,既不能防止也不能对链霉素的降压作用;在给予神经节阻断药(六烷双铵)后,链霉素的降压效应仍然表现.链霉素和二链霉胺均能抑制在位兔心的收缩作用.在脊髓大白鼠和脊髓猫标本上,链霉素仍有降压作用.链霉素在降低麻醉猫血压时,猫瞬膜对颈上交感神经节前纤维刺激的反应减弱.这些结果表明,链霉素的降压机制主要是由于对心脏的抑制作用和神经节的阻断作用.此外,链霉素的降压作用与其所含杂质二链霉胺有一定关系.     

The 5-hydroxytryptamine-like actions of 5,6-dihydroxytryptamine

1. With isolated preparations of rat stomach fundus as well as of duodenum and ileum of rats and guinea-pigs, 5,6-dihydroxytryptamine and 5,6-diacetoxytryptamine caused a contraction which was antagonized by methysergide and lysergic acid diethylamide (LSD), but not by atropine. Pretreatment of the animals with reserpine did not decrease the effect of the two indoleamines on the isolated ileum and duodenum.2. In anaesthetized guinea-pigs, 5,6-dihydroxytryptamine and its diacetyl derivative caused bronchoconstriction which was antagonized by methysergide, but not modified by pretreating the animals with reserpine.3. In anaesthetized cats, 5,6-dihydroxytryptamine had, in general, a hypotensive effect which was reversed by hexamethonium.4. 5,6-Dihydroxytryptamine also caused aggregation of isolated rabbit and human platelets and inhibited the platelet aggregation induced by 5-hydroxytryptamine (5-HT) plus adrenaline.5. The pattern of action of 5,6-hydroxytryptamine and 5,6-diacetoxytryptamine was qualitatively the same as that of 5-HT, but the potency of the compounds decreased in the order 5-HT, 5,6-dihydroxytryptamine, 5,6-diacetoxytryptamine both in vitro and in vivo.6. It is concluded that 5,6-dihydroxytryptamine and its diacetyl derivative stimulate postsynaptic 5-HT receptors, but that their effect is weaker than that of 5-HT.     

The inhibitory action of morphine on the contraction of the longitudinal muscle coat of the isolated guinea-pig ileum

Morphine (0.05 to 0.1 μg./ml.) markedly inhibited the contractions of the isolated guinea-pig ileum caused by nicotine, barium, and 5-hydroxytryptamine while the actions of acetylcholine, carbachol, and histamine were affected only a little. Atropine (0.025 to 0.05 μg./ml.) had a similar effect, in addition to its known effects on acetylcholine and carbachol contractions. Morphine had no additional effect on the inhibitory action of atropine, while in the presence of morphine, atropine had a significant additional inhibitory action only on the contraction caused by nicotine.

The action of barium was complex. It caused contractions of a rhythmic type alternating with relaxations, a pattern which is similar to that produced by the emptying phase of the peristaltic reflex; these oscillations were inhibited by hexamethonium. On the other hand, that part of the sustained barium contraction which was inhibited by morphine may be explained by an action on the nerve cells innervating the muscle fibres (motor neurones). Similarly, the morphinesensitive component of the 5-hydroxytryptamine (5-HT) contraction was probably also due to an action on the motor neurones. The morphine-insensitive contractions of barium, 5-HT, and nicotine were believed to be caused by a direct action on the muscle fibres.

The morphine inhibitors, nalorphine and levallorphan, had different effects with the different agonists. Their morphine-like action was particularly pronounced on the effect of 5-HT, which they antagonized, while their morphine-protecting action was most strongly present on the effect of nicotine.

     

The inhibitory actions of prostaglandins on respiratory smooth muscle

Prostaglandin E₁, in concentrations as low as 1 ng/ml., relaxed isolated tracheal muscle from cat, monkey, rabbit, guinea-pig and ferret. Tracheal muscle from the cat, monkey and rabbit did not exhibit inherent tone and the effect of prostaglandin E₁ on these preparations was seen only after a sustained contraction had been produced by a previous dose of acetylcholine or of another agonist. Prostaglandins E₂, E₃ and F_1α also relaxed isolated cat tracheal muscle which had been stimulated by acetylcholine: their activities relative to that of prostaglandin E₁ were, respectively, 1.0, 0.2 and 0.002. In the anaesthetized cat prostaglandin E₁ increased lung “resistance to inflation” (presumably comparable to bronchial resistance) and the heart rate. In the anaesthetized rabbit and guinea-pig, prostaglandin E₁ antagonized the rise in resistance to inflation of the lungs obtained after vagal stimulation or after the intravenous injection of histamine; it sometimes lowered the resistance to inflation in these species. The possibility that prostaglandin may have a local physiological role in the control of bronchial smooth muscle tone is discussed.     

The mechanism of the pressor responses to physostigmine in the rat and their modification by mebutamate and amylobarbitone

Pressor responses to intravenous injections both of physostigmine and of pilocarpine were smaller in rats anaesthetized with either mebutamate or amylobarbitone than in rats anaesthetized with urethane. The response to electrical stimulation of the hypogastric nerve in the isolated hypogastric nerve-vas deferens preparation was diminished by mebutamate and by amylobarbitone, but not by urethane. Similar results were obtained with the cat isolated splenic nerve-spleen preparation. In the rat anaesthetized with urethane, pressor responses to physostigmine were only partially antagonized by hexamethonium but were completely abolished during “depolarizing” ganglionic block by nicotine or tetramethylammonium. It is suggested that, in addition to the central mechanism, there is a peripheral component in the pressor action of physostigmine and in the antihypertensive actions of mebutamate and amylobarbitone.     

Pharmacological and electrophysiological studies of morphine and enkephalin on rat supraspinal neurones and cat spinal neurones

1 The actions of morphine, methionine and leucine enkephalin, administered electrophoretically, were studied on supraspinal neurones in the cortex and brainstem of the rat anaesthetized with urethane and on spinal Renshaw cells and dorsal horn interneurones in the cat anaesthetized with pentobarbitone.

2 The majority of Renshaw cells and cortical and brainstem neurones were excited by all three compounds although some supraspinal neurones were depressed.

3 Naloxone reversibly antagonized both excitatory and depressant actions of morphine and enkephalin. Acetylcholine-induced excitation but not amino acid-induced excitation was also antagonized by naloxone.

4 Neither morphine nor the enkephalins had any naloxone-reversible action on dorsal horn neurones when ejected from conventional multibarrelled electrodes. However, morphine but not enkephalin, administered into the substantia gelatinosa region of the spinal cord selectively reduced responses to noxious stimuli of neurones in deeper laminae. Naloxone administered into the same region antagonized this action of morphine.

5 Intravenous morphine also antagonized responses of dorsal horn neurones to noxious stimuli and subsequent intravenous naloxone reversed this effect.

6 It was concluded that the excitatory and inhibitory effects of morphine and enkephalin on central neurones may be mediated by actions on different opiate receptors and that depression of noxious responses of dorsal horn neurones may be relevant to the analgesic action of morphine.

     

Effects on muscle of a toxin from indian cobra (Naja naja naja) venom

—The mode of action of a purified toxin from Naja naja naja (Indian cobra) venom was investigated in frog rectus abdominis muscle, chick biventer cervicis muscle, cat tibialis anterior muscle (close-arterial) and in both innervated and denervated rat diaphragm muscle preparations. The toxin inhibited the acetyl-choline responses of rectus abdominis muscle. The inhibition was antagonized by neostigmine and increasing concentrations of acetylcholine, suggesting a competitive binding of the toxin to cholinergic receptors. The toxin, even at high doses, did not produce depolarizing contractures in chronically denervated diaphragm, biventer cervicis muscle and rectus abdominis muscle preparations. In both cat tibialis anterior and denervated diaphragm muscles, the toxin abolished the acetylcholine sensitivity of the muscles at a faster rate than its effects on muscle contraction, suggesting a preferred action on the motor end-plate. A well-maintained tetanic contraction and very poor post-tetanic potentiation was observed in all preparations treated with toxin, indicating an atypical Wedensky inhibition. Anti-curare agents, such as K⁺ and Ca²⁺, were ineffective in antagonizing the curare-like neuromuscular block in phrenic nerve-diaphragm preparations. A frequency-independent neuromuscular block observed in these nerve-muscle preparations was suggestive of the absence of a possible presynaptic effect. These results demonstrate that although the neurotoxin in some cases can imitate d-tubocurarine, its neuromuscular blocking activity is different from that of curare in many respects.     

GABAA and GABAB receptor-mediated effects in guinea-pig ileum

1 The effects of γ-aminobutyric acid (GABA) and related substances were examined in guinea-pig ileum longitudinal muscle.

2 GABA at doses ranging from 10^-7 M to 3 × 10^-6 M elicited a relaxation while at higher doses (3 × 10^-6 M — 10^-4 M), as previously described, it caused a contraction followed by relaxation.

3 GABA-induced relaxation was bicuculline-insensitive, was mimicked by (-)-baclofen but not by homotaurine and muscimol. The effect of baclofen was stereospecific. GABA- and (-)-baclofen-induced relaxations were dose-dependent and their ED₅₀ values were similar. A specific cross-desensitization occurred between GABA and (-)-baclofen.

4 The bicuculline-insensitive relaxation induced by GABA and (-)-baclofen was prevented by tetrodotoxin and hyoscine but not by phentolamine plus propranolol, naloxone or theophylline.

5 In preparations in which the muscle tone was raised by histamine or prostaglandin F_2α, GABA and (-)-baclofen induced relaxation to the same extent as before increasing the tone. If the tone was raised by DMPP, a greater bicuculline-insensitive relaxation occurred.

6 Contraction caused by GABA was bicuculline-sensitive and was mimicked by homotaurine and muscimol. Contraction was dose-dependent and muscimol was about three times more potent than GABA or homotaurine. A specific cross-desensitization occurred between the contractile effects of GABA and those of homotaurine or muscimol.

7 Bicuculline competitively antagonized the contractile effects of GABA, homotaurine and muscimol and gave closely similar pA₂ values. The slope of the Schild plot for the above drugs was near 1, confirming the competitive nature of the antagonism.

8 The bicuculline-sensitive contraction induced by GABA, homotaurine and muscimol was abolished by tetrodotoxin and was non-competitively antagonized by hyoscine, while it was unaffected by hexamethonium, mepyramine and methysergide.

9 It is concluded that two receptors mediate the GABA effects in guinea-pig ileum: a bicuculline-sensitive GABA_A receptor, which elicits contraction through an excitatory action on cholinergic post-ganglionic neurones; and a bicuculline-insensitive GABA_B receptor which causes relaxation through an inhibitory presynaptic action on cholinergic post-ganglionic neurones. We confirm that GABA, homotaurine and muscimol are GABA_A agonists, while GABA and (-)-baclofen are GABA_B agonists.

     

Relative actions of quaternary methyl derivatives of tyramine, dopamine and noradrenaline

Tyramine methiodide and dopamine methobromide have greater pressor effect (three- to five-times) in the spinal cat than the parent amines. Noradrenaline methochloride has little pressor effect. Dopamine methobromide is about four times as potent as nicotine; tyramine methiodide is about equiactive to nicotine; and noradrenaline methochloride has only one-tenth the potency of nicotine. Their pressor effects are usually abolished by hexamethonium but in some experiments the effect of noradrenaline methochloride persisted and was then abolished by tolazoline. Injected intravenously into the cat anaesthetized with chloralose, each of the three quaternary derivatives contracts the nictitating membrane; dopamine methobromide is again the most active, having more than six times the potency of nicotine. When the contractions of the nictitating membrane are induced by continuous stimulation of the preganglionic fibres of the cervical sympathetic nerve, intravenous injection of the quaternary derivatives of tyramine and dopamine has a biphasic effect; there is a block on which a contraction of the membrane appears to be superimposed. Noradrenaline methochloride produces only a further contraction of the membrane. On the isolated rectus abdominis muscle preparation of the frog, dopamine methobromide is the most active in contracting the muscle, being about twelve times as active as nicotine; noradrenaline methochloride is weakest, having only one-hundredth the activity of nicotine. These effects are antagonized by hexamethonium. On the isolated phrenic nerve-diaphragm preparation of the rat, the quaternary derivatives of tyramine and dopamine each have neuromuscular blocking properties, 0.7- and 3-times respectively that of nicotine. Noradrenaline methochloride has no effect. In the sciatic nerve-tibialis preparation of the cat, the quaternary derivatives of tyramine and dopamine are approximately equipotent in producing neuromuscular paralysis, having about three times the activity of nicotine and one-fifth that of suxamethonium. These effects are not antagonized either by neostigmine or by edrophonium. Noradrenaline methochloride has no neuromuscular blocking effect. The nicotine-like properties of these quaternized sympathomimetic amines are discussed. It is of interest that the presence of an hydroxyl group attached to the β-carbon atom of the side-chain greatly reduces nicotine-like activity. By comparison, choline had about one forty-fifth the pressor activity of ethyltrimethylammonium.     

Involvement of cholinergic neurons in orexin-induced contraction of guinea pig ileum

The mechanism underlying orexin-induced contraction was examined in isolated preparations of guinea pig ileum, in relation to cholinergic transmission. Orexin-A caused contraction of ileal strips in a concentration-dependent manner. 1-(2-Methylbenzoxazol-6-yl)-3-[1,5]napthyridin-4-yl-urea hydrochloride (SB-334867-A) antagonized the orexin-A-induced contraction, with no effects on the acetylcholine-induced contraction and twitch contractions. The orexin-A-induced contraction was inhibited by tetrodotoxin and atropine, but not by hexamethonium, an antagonist of vasoactive intestinal peptide and a mixture of 5-hydroxytryptamine receptor antagonists. Orexin-A evoked an outflow of [3H]acetylcholine from the ileal strips preincubated with [3H]choline, in a concentration-dependent manner, and the orexin-A-evoked outflow was inhibited by tetrodotoxin, indicating that the outflow of [3H]acetylcholine originates from the nerve terminals. The orexin-A-evoked outflow of [3H]acetylcholine was antagonized by SB-334867-A. Thus, orexin-A evokes the release of acetylcholine from the enteric cholinergic neurons due to stimulation of the orexin-1 receptors and then causes contractions of guinea pig ileum.     

GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein.

1. We describe the actions of a novel and selective 5-HT1-like receptor agonist, GR43175, in a range of isolated tissue preparations containing different 5-hydroxytryptamine (5-HT) receptor types. 2. GR43175 was a potent agonist at 5-HT1-like receptors mediating contraction of the dog isolated saphenous vein and also at those inhibiting neuronally mediated contractions in the same preparations. For both actions, GR43175 was approximately four times weaker than 5-HT. 3. GR43175 was devoid of agonist properties at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein. 4. GR43175 was devoid of agonist properties at 5-HT2 receptors mediating contraction of the rabbit isolated aorta, pig coronary artery, greyhound coronary artery and beagle femoral artery. 5. GR43175 was devoid of agonist properties at 5-HT3 receptors mediating depolarization of the rat isolated vagus nerve. 6. The contractile response to GR43175 in the dog isolated saphenous vein was selectively antagonized by methiothepin but was resistant to antagonism by the 5-HT2 receptor blocking drug ketanserin and the 5-HT3 receptor blocking drug MDL 72222. Methiothepin antagonized the contractile action of 5-HT and GR43175 to an equal extent suggesting that both agonists act at the same receptor. 7. The results demonstrate that GR43175 is a highly selective agonist for the 5-HT1-like receptors found in the dog saphenous vein. The absence of an action of GR43175 at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein provides further evidence that 5-HT1-like receptors are heterogeneous.     

The effect of cholinesterase inhibitors and corticosteroids on rat nerve-muscle preparations treated with hemicholinium-3

Corticosteroids improve muscle function impaired by hemicholinium-3 (HC-3). The effects of cholinesterase inhibitors either alone or in combination with the glucocorticoid dexamethasone were studied on nerve-muscle preparations treated with HC-3, both in vivo and in vitro. Administered simultaneously with HC-3 (80 μg/kg by i.p. injection, physostigmine (250–1500 μg/kg) caused a significant, dose-dependent reversal of the neuro-muscular transmission block caused by HC-3 in the sciatic nerve-tibialis anterior muscle preparation of the anaesthetized rat, stimulated at a rate of 10 Hz. The HC-3-blocked neuromuscular transmission was also antagonized by neostigmine (125 and 250 μg/kg). Under the same conditions physostigmine (1000 μg/kg) potentiated the effect of dexamethasone. After i.p. injection of physostigmine (125–1000 μg/kg) and neostigmine (62.5–250 μ/kg) respectively, the LD₅₀ in rats was significantly increased. With physostigmine a sharp maximum was found at 250 μg/kg. Neostigmine, and to a lesser extent physostigmine antagonized the neuromuscular transmission inhibited by HC-3 in the in vitro phrenic nerve—diaphragm preparation of the rat. The HC-3-induced inhibition of both uptake of choline and its incorporation into acetylcholine was antagonized by physostigmine and neostigmine. This antagonism was not altered in the presence of dexamethasone 0.2 μM. The possible implications of these findings, and the mechanism underlying the effects seen with corticosteroids and cholinesterase inhibitors are discussed. It is concluded that under certain circumstances a nerve-muscle preparation treated with HC-3 may be an adequate model for myasthenia gravis.     

The response of cat airways to histamine in vivo and in vitro.

The effects of histamine have been examined in anaesthetized cats and on cat cat isolated lung parenchyma strip. Histamine infused intravenously for 2 min produced a small and inconsistent effect on central airways and a small but consistent constriction of peripheral airways. Histamine bronchoconstriction of the central airways was unmasked by non-selective and beta 2-adrenoceptor blockade but not by beta 1-adrenoceptor blockade. This bronchoconstriction was antagonized by atropine but not by cimetidine or prazosin. Bronchoconstriction of the peripheral airways was not affected in a dose-related manner by beta-adrenoceptor blockade. The bronchoconstriction was antagonized by mepyramine but not by atropine or prazosin. beta-Adrenoceptor antagonists produced a bell-shaped dose-response curve on histamine contractions in cat isolated lung parenchyma strip. Strips of lung parenchyma obtained from reserpine-treated cats produced a larger contraction to histamine which was not potentiated by propranolol. It is concluded that in the central airways, histamine bronchoconstriction produced by an action on irritant receptors is masked by an action on beta 2-adrenoceptors of catecholamines released locally and from the adrenal glands. In the peripheral airways, histamine bronchoconstriction is mediated by H1-receptors and beta 2-adrenoceptor blockade may either potentiate or antagonize the histamine response depending on the concentration.     

Effects of some guanidine derivatives on neuromuscular and ganglionic transmission

The anticurare activity of some guanidine derivatives has been studied using the fowl sciatic nerve-gastrocnemius muscle preparation and the cat sciatic nerve-gastrocnemius and tibialis anterior muscle preparations. Among the compounds tested, and in decreasing order of potency, were NN-dimethylguanidine, N-methylguanidine, guanidine and N-aminoguanidine which antagonized or prevented tubocurarine or gallamine triethiodide-induced paralysis. None of the derivatives antagonized the effects of suxamethonium or decamethonium. NN-Dimethylguanidine, N-methylguanidine and guanidine antagonized or prevented the curare-like effects of magnesium without altering the activity of hemicholinium. At high doses NN-dimethylguanidine induced a decamethonium-like spastic paralysis in the fowl sciatic nerve-gastrocnemius muscle preparation. NN-Diethylguanidine, however, induced a tubocurarine-like flaccid paralysis. The derivatives possessing anticurare activity were also studied using the cat superior cervical ganglion-nictitating membrane preparation to check their possible effects against ganglionic blocking agents. Only guanidine antagonized or prevented the effects of hexamethonium, pentolinium and mecamylamine; it had no effect on the actions of pempidine and chlorisondamine. NN-Diethylguanidine was the only compound in the series to show a ganglionic blocking action.     

Some cocaine-like actions of 3-phenoxypropylguanidine

In anaesthetized cats 3-phenoxypropylguanidine caused a contracture of the nictitating membrane, a dilatation of the pupil and a fall followed by a rise in the arterial blood pressure. In spinal preparations of cats the initial fall in blood pressure was usually absent and the rise in blood pressure subsided to a steady level, which was about 10 mm Hg above the initial pressure. The pressor action and the contracture of the nictitating membrane were inhibited by phenoxybenzamine and by previous treatment with reserpine, but were not abolished by adrenalectomy and bretylium. 3-Phenoxypropylguanidine potentiated the actions of adrenaline and noradrenaline, increased the blood glucose concentration of the rabbit and decreased the appetite of the cat. The action of tyramine on the cardiovascular system was inhibited by 3-phenoxypropylguanidine, but the stimulant action of tyramine on the nictitating membrane of the cat was not abolished by this substance. Although 3-phenoxypropylguanidine produced a local anaesthesia of long duration in guinea-pig skin, it failed to anaesthetize the rabbit cornea. The responses to stimulation of the preganglionic cervical sympathetic nerve of the cat and the great auricular nerve of the rabbit ear were not abolished by 3-phenoxypropylguanidine; neither did this substance abolish the nicotinic action of acetylcholine in atropinized cats. Contractions of the rat fundus to tryptamine and 5-hydroxytryptamine were antagonized by 3-phenoxypropylguanidine, but were potentiated by cocaine.     

GABAA-receptor-mediated inhibition of the delayed increase in intragastric pressure to stimulation of vagal afferent fibres in cats.

1. The possible involvement of gamma-aminobutyric acidA (GABAA)- and GABAB-receptors in the inhibitory effects of GABA on the delayed increase in intragastric pressure of the stomach to stimulation of vagal afferent fibres in cats was studied. 2. Cats were anaesthetized with pentobarbitone-gallamine and pretreated with hexamethonium. GABA inhibited the hexamethonium-resistant delayed contraction of the stomach in a dose-dependent manner. Such effects of GABA were antagonized by both bicuculline and picrotoxin. 3. Muscimol, a GABAA-receptor agonist, mimicked the inhibitory effects of GABA and the effects of muscimol were antagonized by bicuculline and picrotoxin. The ID50 of muscimol was 10 times less than that of GABA. 4. In contrast to muscimol, baclofen, a GABAB-receptor agonist did not mimic the inhibitory effects of GABA. 5. The present experiments demonstrate that GABAA-receptors are involved in the inhibitory action of GABA on the delayed contraction of the stomach to vagal afferent stimulation.     

An anti-curare effect of hexamethonium at the mammalian neuromuscular junction

1. Experiments were performed on the isolated phrenic nerve and diaphragm preparation of the rat.2. In preparations partly blocked with (+)-tubocurarine, the twitch amplitude increased after hexamethonium. This enhancement was not seen in preparations partly blocked with Mg(++) or with gallamine. High concentrations of hexamethonium produced failure of contraction.3. Extracellular endplate potentials were recorded from blocked preparations. The administration of hexamethonium resulted in an increased amplitude of these potentials only in curarized muscle.4. Hexamethonium had no anticholinesterase activity nor did it depolarize muscle cells or increase the quantal release of transmitter.5. It is concluded that hexamethonium exerts a specific anti-curare action. Experiments on the recovery of the twitch after washing out antagonists indicate that this process is limited by diffusion. The difference in rates of diffusion of hexamethonium and (+)-tubocurarine does not account for their interaction. The basis of the anti-curare action of hexamethonium is discussed.     

Observations on the efficacy of oral hyoscine N-butyl bromide

Hyoscine N-butyl bromide (Buscopan) antagonized the spasmogenic action of acetylcholine on guinea-pig isolated ileum, having a pA₂ of 7·8. The drug also had intestinal antispasmodic activity in the anaesthetized cat after either parenteral or enteral administration. With the enterally administered drug larger doses were required, but the effects were longer lasting. Enterally administered in conscious dogs the drug sometimes produced a small increase in heart rate.     

A ganglion stimulating action of neostigmine

The actions of neostigmine on transmission in the superior cervical ganglion have been investigated by means of the nictitating membrane preparation in the anaesthetized cat. Intravenous injections of neostigmine produced a rapid and often complete reversal of hexamethonium block, whereas eserine had no effect. This reversal by neostigmine was obtained regularly even after large doses of eserine or dyflos, but was sometimes brief. In ganglia perfused with heparinized plasma containing neostigmine (10^-8 to 10^-4), there was no potentiation of the responses to maximal stimulation of the preganglionic nerve. Intra-arterial injections of neostigmine to both normal and preganglionically denervated ganglia produced first a potentiation of the responses to nicotine, then, with larger doses, a contraction of the nictitating membrane and, concurrently, a depression of the responses to nicotine. These results are consistent with the view that neostigmine exerts a direct stimulant action on the ganglion, which is distinct from its anticholinesterase action.     

The effects on cardiac muscle and nerve of a fluorinated decahydroquinoline derivative, L7810, rapidly absorbed after oral administration

1. L7810 (4-carbamoyloxy-1-(4-(4-fluorophenyl)-4-oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1·75 times that of procaine.

2. L7810 protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation and increased the lethal dose of ouabain.

3. L7810 reduced the rate of rise of intracellularly recorded action potentials in rabbit isolated atria; the resting potential was not affected, but the duration of the action potential was prolonged.

4. Unlike most drugs with local anaesthetic properties L7810 did not depress contractions in isolated atria but increased them.

5. L7810 reduced the spontaneous frequency, maximum follow frequency and conduction velocity of rabbit isolated atria.

6. L7810 had no blocking action on the chronotropic or positive inotropic actions of isoprenaline on isolated atrial muscle.

7. In anaesthetized dogs L7810 caused a small dose-related bradycardia, and a large dose-related decrease in peripheral vascular resistance. There was no blockade of the effects of isoprenaline on heart rate or peripheral blood flow.