Neuromuscular blocking properties of some bistropinium esters

The neuromuscular blocking, anti-acetylcholine and ganglion blocking properties of two series of bistropinium esters were examined. The neuromuscular blocking activities of the mandelic acid esters of NN'-polymethylenebis(tropinium halides) were found to depend upon the number of carbon atoms (n) in the linking chain. Potency was enhanced more than 50 times as n was increased from 2 to 7. Compounds in which n equalled 7, 8, 9, 10 and 12 differed little in activity, but were generally more potent than tubocurarine in cats and rabbits. A peak of ganglion blocking action was obtained at the pentamethylene member. Esterification enhanced the feeble neuromuscular blocking properties of NN'-decamethylenebis(tropinium halide), the mandelic acid ester being more effective than the tropic, benzoic or phenylacetic acid esters in cats and rabbits. When two benzoic or mandelic acid esters of tropine were linked through their nitrogen atoms by a phenylenedimethyl grouping (-CH₂.C₆H₄.CH₂-), meta substitution was more effective than was ortho or para in producing neuromuscular block. The effectiveness of esterifying acids in m-phenylenedimethyl derivatives decreased in the following order, phenylacetic> tropic or mandelic>benzoic>acetic and diphenylacetic.     

Neuromuscular effects of some opioid agonists and antagonists

The effects of morphine, pethidine, (-) naloxone, N-methylnaloxone, naltrexone and levallorphan on acetylcholine-induced contraction of the toad rectus were studied. The drugs were shown to inhibit the contraction, and their inhibitory effect was suggested to be partly mediated via a peripheral opiate binding site. The depression of acetylcholine-induced contraction by levallorphan and dextrallorphan might indicate possible involvement of stereospecific binding sites, as the latter required a significantly higher concentration to produce the same magnitude of depression. Statistical analysis of the slope of the computer-plotted dose-response of acetylcholine in the presence and absence of each of the opioids indicates that these drugs can be classified into four categories. Morphine and naltrexone each formed a class of its own; (-) naloxone, N-methylnaloxone and pethidine formed another class; levallorphan and dextrallorphan formed the fourth class. The classification of the opioids into four categories reveals the possible existence of multiple opiate binding sites on the skeletal muscle. The significance of each of the sub-types of binding sites in the contraction of skeletal muscle and the mechanism by which it affects the contraction remains to be investigated.     

The ganglion blocking and vagolytic actions of three short-acting neuromuscular blocking drugs in the cat

Three recently-introduced short-acting neuromuscular blocking drugs with non-depolarizing mechanisms of action, stercuronium, dacuronium and AH8165 (1,1′-azobis [3-methyl-2-phenyl-1H-imidazo (1, 2a) pyridinium] dibromide) have been tested in the anaesthetized cat on the responses of the nictitating membrane to stimulation of the cervical nerve, and of the heart to vagal stimulation. The effects of the three drugs at the superior cervical ganglion and at the cardiac neuroeffector junction have been compared with their neuromuscular blocking effects. At doses lower than those required to block neuromuscular transmission all three compounds possessed a selective atropine-like action at the cardiac vagus neuroeffector junction in that they inhibited the bradycardia produced by vagal stimulation and by acetyl-β-methylcholine, whilst the depressor action of acetyl-β-methylcholine was unaffected. The ratios of the doses of the drugs to block the responses of the preganglionically-stimulated nictitating membrane and of the tibialis anterior muscle were 16m?7 for stercuronium, 8m?5 for dacuronium and 3m?8 for AH8165. The greater ganglion-blocking activity of AH8165 was reflected in the depressor action of the compound, whereas the weak ganglion-blocking actions of stercuronium and dacuronium were insufficient to mask the tachycardia and pressor effect caused by their blocking action on the cardiac vagus neuroeffector junction.     

Neuromuscular blocking agents block carotid body neuronal nicotinic acetylcholine receptors

Neuromuscular blocking agents predominantly block muscle type nicotinic acetylcholine receptors as opposed to the neuronal type. However, there is growing evidence that neuromuscular blocking agents have affinity to some neuronal nicotinic acetylcholine receptors. The carotid body chemoreceptor as the essential oxygen-sensing cell, relies on cholinergic signalling. Atracurium and vecuronium impair carotid body chemoreceptor activity during hypoxia. Here, we characterize atracurium and vecuronium as antagonists at nicotinic receptors of the carotid body chemoreceptor. Isolated rabbit carotid body preparations with carotid sinus nerve were used, and chemoreceptor activities were recorded. There was a concentration-dependent reduction in the chemoreceptor responses to nicotine, with an IC(50) to 50 microg nicotine of 3.64 and 1.64 microM and to 500 microg nicotine of 27.00 microM and 7.29 microM for atracurium and vecuronium, respectively. It is concluded that atracurium and vecuronium depress nicotine-induced chemoreceptor responses of the carotid body in a dose-dependent fashion.     

Ganglion blocking properties of some bispyridinium soman antagonists.

Various doses of several bispyridinium compounds (HS-6, HI-6, HGG-12, HGG-42, and SAD-128) known to protect animals against the irreversible cholinesterase inhibitor soman were examined to determine their effects on the cardiovascular and respiratory system of cats. Although the potency varied considerably all of the compounds tested lowered the blood pressure, which appeared to be the result of ganglion blocking properties as determined by their reduction of the pressor response to dimethylphenylpiperazinium and the blockage of the contraction of the preganglionically stimulated cat nictitating membrane. Some of the compounds caused cessation of respiration at much lower doses than others but did so at doses greater than those causing ganglion blockage.     

Inhibition by substance P of some peripheral actions of acetylcholine in the cat

1 The effect of substance P on contractions of the nictitating membrane and pressor responses to acetylcholine (ACh) and dimethylphenyl-piperazinium (DMPP) which were mediated via nocotinic receptors was studied in cats anaesthetized with chloralose.

2 Substance P (2-20 nmol) injected into the lingual artery giving estimated concentrations in arterial blood of 10^-6 to 10^-5 M, or intravenously giving estimated concentrations in blood of 10^-8 to 10^-7 M, reduced hexamethonium-sensitive but not atropine-sensitive responses.

3 The pressor effects of ACh and DMPP injected intra-arterially in atropinized and non-atropinized cats respectively were consistently attenuated by substance P given intra-arterially or intravenously.

4 The contractile effect of ACh in atropinized and of DMPP in non-atropinized cats was attenuated by substance P injected intra-arterially but only rarely when the polypeptide was injected intravenously.

5 The depressor effects of substance P per se were variable in magnitude and duration as were the inhibitory effects upon nicotinic receptors. The depressor and inhibitory effects of substance P were unrelated.

6 There was desensitization to all of these effects of substance P which probably contributed to the variation in the magnitude of the effects observed.

7 Substance P had no effect on muscarinic actions of acetyl-β-methylcholine on the nictitating membrane or blood pressure.

8 The results are discussed in relation to the ubiquity of the modulatory actions of substance P on nicotinic receptors and in relation to the possible physiological significance of the action.

     

Further studies on the adrenergic neuron blocking activity of some -adrenoceptor antagonists and guanethidine

The effects of low (0.2) and high (20 μg ml^?1) concentrations of (±)- and (+)-propranolol, (±)-, (+)- and (-)-sotalol and guanethidine were tested for their ability to reduce responses to sympathetic stimulation in the isolated vas deferens preparation from the guinea-pig. At 0.2 μf ml^?1 all drugs produced a slowly developing reduction in the responses to sympathetic stimulation while responses to noradrenaline were largely unchanged. The blockade, which was similar in extent in all six compounds, was reversed by (+)-amphetamine but not by washing. With high concentrations of and (±)-propranolol and guanethidine, the block was rapid in onset and rate and responses to noradrenaline were potentiated. The block was reversed by washing and unaffected by (+)-***amphetamine. Sotalol and its isomers, which possess little non-specific depressant activity, had qualitatively similar actions at 0.2 and 20 μg ml^?1. At the latter concentration responses to noradrenaline were potentiated. The results suggest that low concentrations of the β-adrenoceptor antagonists produce a blockade which is typical of guanethidine-like drugs. At high concentrations non-specific depressant (local anaesthetic) actions of propranolol and its isomers are largely responsible for the blockade. A similar mechanism may also operate when high concentrations of guanethidine are used.     

Neuromuscular blocking activity of aminoglycoside antibiotics

The aminoglycoside antibiotics possess neuromuscular blocking activity; the potency of those antibiotics tested appears to be as follows: gentamicin greater than streptomycin greater than amikacin greater than sisomicin greater than kanamycin = tobramycin greater than kanendomycin = dibekacin. The neuromuscular blockade produced by these antibiotics is not reversed by neostigmine, whereas it is reversed by calcium. Calcium not only has the ability to restore the neuromuscular transmission but also to exert protective action against the neuromuscular blocking activity of aminoglycoside antibiotics; these antibiotics are also potentially capable of interacting with non-depolarizing muscle relaxant drugs (d-tubocurarine, pancuronium) or propranolol, a beta-adrenergic receptor blocking agent. This interaction results in respiratory depression and/or prolonged apnoea. Our findings lead to the assumption that amino-glycoside antibiotics are involved in the process of acetylcholine release by nerve impulses, antagonizing calcium ions.     

Actions of some cholinergic antagonists on fast-twitch and slow-twitch skeletal muscle of the cat

1. The anticholinergic drug N-ethyl-2-pyrrolidylmethylcyclopentylphenyl glycollate (PMCG) has been studied for its effects on the contraction of fast-twitch (flexor hallucis longus, FHL) and slow-twitch (soleus) muscles in the cat.2. In both muscles lower doses (0.25 to 10 mg intra-arterially) potentiated and higher doses (10 mg and above) depressed twitches produced by indirect stimulation. Similar effects were obtained in directly stimulated muscles.3. The effects of the drug on muscles stimulated repetitively were dependent on both dose and frequency of stimulation. Doses which potentiated twitches also potentiated low frequency tetani (5-30 Hz for soleus; 10-50 Hz for FHL). There was a depression and non-maintenance of higher frequency tetani (80 Hz and above for soleus; 150 Hz and above for FHL).4. Both atropine and caramiphen had similar dose dependent potentiating and depressant actions. Hyoscine acted similarly in some cats; in others it had only a depressant action.5. It is suggested that the potentiating actions of PMCG, caramiphen, atropine and hyoscine are due to a direct musculotropic action. The depressant actions resulting from higher doses are due, in part, to a curare-like action and in part to a direct action on the muscle fibres.     

Effects of narcotic analgesics and antagonists on the in vivo release of acetylcholine from the cerebral cortex of the cat

1. In cats under light allobarbitone anaesthesia, the effects of intravenous injections of narcotic and non-narcotic analgesics, of a general depressant, and of narcotic antagonists were investigated on the spontaneous release of acetylcholine (ACh) from the surface of the sensorimotor cortex.2. The narcotic analgesics morphine (0.1, 1.0 and 5 mg/kg), meperidine (1.0 and 2.0 mg/kg), methadone (1.0 mg/kg) and codeine (5.0 and 10.0 mg/kg) greatly reduced ACh release.3. The non-narcotic analgesics pentazocine (1.0 and 2.0 mg/kg) and propoxyphene (5.0 and 10.0 mg/kg) as well as the depressant chlorpromazine (0.25, 0.5 and 1.0 mg/kg) also greatly reduced ACh release.4. Two of the three narcotic antagonists examined, levallorphan (0.1, 1.0 and 5 mg/kg) and nalorphine (1.0 mg/kg) had the property of reducing ACh release. They were thus partial agonists. With levallorphan the greatest reduction occurred with the smallest dose injected and the effect was regularly obtained, whereas with nalorphine a reduction was obtained in some experiments only. The third, naloxone, was a specific narcotic antagonist and did not reduce the ACh release in any dose (0.01, 0.1, 0.5 and 1.0 mg/kg) examined. In a dose of 1.0 mg/kg it actually produced a small increase in Ach release.5. Naloxone (0.1-1.0 mg/kg) restored the reduction in ACh release produced by the narcotic analgesics and by the partial agonist levallorphan. It partially restored the reduction produced by the non-narcotic analgesics and by nalorphine, but had no effect on the reduction produced by chlorpromazine.6. The relevance of these results with regard to analgesia and to the narcotic abstinence syndrome is discussed.     

Microiontophoresis of acetylcholine, histamine and their antagonists on neurones in the medial and lateral vestibular nuclei of the cat

Cats with midcollicular decerebration and the cerebellum removed were tested with controlled acceleration to identify neurones in the medial vestibular nucleus and lateral vestibular nucleus which responded to motion. The actions of both cholinergic and histaminergic agents and their antagonists were studied on (1) spontaneously firing cells of the medial and lateral vestibular nuclei which responded to a motion stimulus and (2) other cells located in the medial or lateral vestibular nucleus but whose activity was not modulated by the test motion. lontophoretically applied acetylcholine, methachoiine and carbamylcholine excited neurones in both the medial and lateral vestibular nuclei Acetylcholine-induced excitation was potentiated by physostigmine at dose levels which occasionally initiated a small excitatory response. Iontophoresis of atropine blocked acetylcholine excitation of vestibular cells without altering their response to glutamate. Dihydro-β-erythroidine was ineffective in blocking acetylcholine excitation. Histamine produced marked inhibition of the majority of the cells tested, although several cells were excited by this agent. The H₁-antagonist diphenhydramine was not effective in blocking histamine responses while the H₂-antagonist metiamide effectively blocked histamine inhibition without affecting excitatory responses to acetylcholine. Acetylcholine and histamine produced similar responses from cells modulated by motion and from cells unresponsive to motion. These results suggest that vestibular cells possess both muscarinic cholinergic receptors and histaminergic receptors of the H₂ type.