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W2028263839 abstract "Since the classical work of Crum Brown and Fraser, the curariform action of many onium salts has been recognized, and other activities exerted by these compounds have been described, such as those commonly called nicotine-like or muscarine-like. In the present paper an account is given of the actions of members of a polymethylene bistrimethylammonium series, whose general formula is (CH3)3 N+(CH2)n N+(CH3)3.2I. The compounds will be referred to by the value of n; thus C10 is the decane derivative, where n = 10. Our attention was drawn to the series during a test of the power of the octamethylene compound to liberate histamine. After the injection of a small dose into a cat, there was no depressor response, such as histamine-liberators cause (Macintosh and Paton, 1949); on the contrary, the blood pressure rose. This rise was evidently asphyxial, since the respiration had simultaneously ceased; but there were no gasps or convulsive movements such as usually accompany asphyxia, and the sequence of events suggested some form of neuromuscular block. This series has also been independently studied by Barlow and Ing, with whom a simultaneous preliminary report was arranged (Barlow and Ing, 1948a; Paton and Zaimis, 1948a), and who have now reported their results more fully (Barlow and Ing, 1948b). Following a further note (Paton and Zaimis, 1948b), preliminary clinical trials of the decane derivative as a substitute for d-tubocurarine chloride in anaesthesia and convulsion therapy were instituted. These have proved successful, and the name “decamethonium iodide” has been approved by the British Pharmacopoeia Commission as the official name for the compound. Our investigations of the pharmacological actions of these compounds have been chiefly directed to studying their activity in blocking neuromuscular transmission. Particular attention has been paid also to describing how the pharmacological activity varies with the length of the polymethylene chain. Later papers will report more fully experiments on other pharmacological actions. Cats anaesthetized with chloralose (80 mg./kg.), after induction with ether, were used in most of the experiments. For recording the tension of muscle twitch, tibialis anterior was prepared; the preparation was mounted on the Brown-Schuster myograph stand, and an isometric steel spring myograph was used for recording on the smoked drum. The muscle was excited either by slightly supra-maximal shocks to the sciatic nerve through shielded silver electrodes, or directly by induction coil break shocks. The nerve was tied centrally, above the point of stimulation and above the point of entry of its blood supply. Injections were made either intravenously through a cannula tied into the femoral or jugular vein, or by the method of close arterial injection into the anterior tibial artery (Brown, 1938a). A few animals were anaesthetized with pentothal infused at a rate of 0.3–0.5 mg./min., or with ether from an “Oxford vaporizer” adapted for animal use, using 6–7 per cent ether. For experiments on unanaesthetized animals, injections of volumes of 0.01 c.c./g. were made into the tail vein of mice (white, male, weight 18–20 g.) and rats (male, weight 100–150 g.). (The effective dose was that which prevented the animal righting itself when placed on its back.) Rabbits (male, weight 1.5–2 kg.) were used for the continuous infusion head-drop method (Dutta and Macintosh, 1949), or received rapid intravenous injections in the marginal ear vein. Cats, monkeys (Macaca mulatto), and a baboon (Papio anubis) received injections in the saphenous vein. Frogs were tested as described by King (1935). In cats anaesthetized with chloralose, the contraction of the nictitating membrane was recorded on the smoked drum. The membrane was excited to contraction by maximal stimuli applied to the peripheral stump of the cervical sympathetic, cut and separated from the vagus in the neck; a rate of stimulation of 10 per sec. produced a well-sustained contraction. In other experiments, the isolated rabbit intestine preparation described by Feldberg and Lin (1949) was employed. Muscarine-like action was tested on rabbit or guinea-pig small intestine, suspended in Ringer solution containing magnesium chloride (0.004 g./100 c.c.): atropine sulphate (10−7) was used as an antagonist. The frog's rectus abdominis suspended in frog Ringer solution was employed in customary fashion to test for nicotine-like stimulation of skeletal muscle. The spinal cat was prepared as described by Barger and Dale (1910) Feldberg and Lin (1949) for the detection of pressor activity. Anticholinesterase activity was determined using a Warburg manometer, with rabbit's laked washed red cells and acetyl-β-methylcholine (0.027 M) or rabbit plasma and benzoyl choline (0.0055 M) as sources of and substrates for “true” or “pseudo” cholinesterase respectively. The substrate and inhibitor (if any) were placed in the sidearm of the Warburg bottle, so that shaking brought them into simultaneous contact with the enzyme; readings of the manometer were then made every 10 minutes for two hours. The surface tension of aqueous solutions of the compounds against air was measured with a De Nöuy tensionmeter. Values for the surface tension of glass-distilled water of 71.5–72.1 dynes/cm. at 20–23° C. were obtained. Actions on the respiration were recorded at first by discharging the expirations of the animal (by means of light rubber valves) into a large glass vessel from which a fine adjustable leak was provided, and measuring the pressure within it by a sensitive tambour; later measurements were made with the respiration recorder described by Paton (1949a). Blood pressure was measured in the usual way, a cannula coated with silicone and filled with saline containing heparin being inserted into the carotid artery. We are much indebted to Dr. J. A. B. Gray for recording action potentials from the peroneal nerve and tibialis muscle for us in certain experiments. The most notable activity of this series is that possessed by the higher members in causing neuromuscular block. Fig. 1a shows the effect of the intravenous injection of a small dose of C10 (the most active compound in this respect) on the contractions of cat's tibialis muscle excited through its motor nerve. At first the tension is increased, and between the contractions fasciculations of the muscle can be seen. (The other muscles of the animal also exhibit these incoordinated contractions.) Then the twitch tension begins to diminish until, with this dose, the muscular contraction is almost completely abolished. When the muscle is completely paralysed to stimulation through its nerve, it is still capable of responding to direct stimulation (Fig. 2). (a).—Cat, chloralose, 3.7 kg. Record of contractions of tibialis excited by supramaximal shocks to the sciatic nerve every 10 sec. At 1, 0.12 mg. C10 intravenous injection. At 2 and 3, tetanic stimulus to motor nerve, 50/sec. (b) Same experiment, 36 min. later. d-Tubocurarine chloride 0.3 mg. intravenously 5 min. previously. At 4, 0.12 mg. C10 i.v. At 5, 0.24 mg. C10 i.v. . Cat, chloralose, 2.6 kg. Tibialis; nerve shock every 10 sec. At arrow 1, injection of 0.1 mg. C10 i.v. During 2, direct stimulation of muscle. At 3. 1 mg. atropine sulphate i.v. At 4, 0.5 mg. neostigmine methylsulphate i.v. During the progress of such a paralysis the action potential of the motor nerve to tibialis remains completely unimpaired while the muscle action potential and twitch tension dwindle and disappear (Fig. 3A). The site of paralysis, therefore, must be placed in the end-plate region or in the terminal nerve endings. (A).—Cat, chloralose. Supramaximal shock to sciatic nerve every 10 sec. (a, c) Record of action potential of peroneal nerve (preceded by stimulus artifact), (a) before C10; (c) after 100 μg. C10/kg.: and (b, d) record of action potential of tibialis muscle, (b) before C10; (d) after C10. Time = 10 msec. (B) Cat, chloralose, 2.6 kg. Record as in (A) showing repetitive muscle action potential after 50 μg. C10. One possible mechanism for such a paralysis might be abolition of the release of acetylcholine by the nerve endings, as has been described for procaine (Harvey, 1939) and suggested for atropine (Brown, 1937). We have found, however, that the effects of acetylcholine given by close arterial injection are antagonized as much as (or more than) the effect of a nerve volley by a dose of C10, just as they are by curare (Fig. 4). A similar suppression of the response to acetylcholine is shown in Fig. 9. . Cat, chloralose, 2.8 kg. Tibialis: nerve shock every 10 sec. At A, injections of 5 μg. acetylcholine intra-arterially. At C10, 6 μg. C10 injected intra-arterially. . —Cat, chloralose, 2.8 kg. Tibialis: nerve shocks every 10 sec. Intra-arterial injections: (a) At K, 3 mg. KCl. (b) At C10,4 μg. C10; at A, 5 μg. acetylcholine; at K, 3 mg. KCl. The blocking action of C10 therefore cannot be explained by an interference with release of acetylcat's plasma. The plasma was then tested on the cat's blood pressure. During the control period, there was no detectable depressor activity in the effluent; stimulation of the motor nerve at a rate of 50 per sec. for 2 min. caused the release of depressor material in a concentration equivalent to 5 mμg. acetylcholine per c.c. in the effluent, and the activity of this depressor material was abolished by the injection of 0.5 mg. atropine into the assay cat; this release was not prevented by adding C10 to the perfusion fluid to a concentration of 10−5. The fasciculations and the potentiation of the twitch preceding neuromuscular block led us to test these compounds for anticholinesterase activity, since known anticholinesterases produce similar actions; and experiments in this connexion are described below which revealed that C10 and its neighbours possess some activity of this kind. (Later work (Zaimis, 1949) indicates, however, that if this anticholinesterase action plays a part in causing these effects, such a part is small.) The potentiation of the twitch may be considerable, and is best seen with smaller doses of C10, such that the subsequent neuromuscular block is too small to obscure the potentiating process; Fig. 5 exemplifies such an experiment. With still smaller doses, a transient enhancement of the twitch tension may be the only evidence that C10 has been injected. It was necessary, therefore, to test whether the neuromuscular block might even be choline. Further, since these compounds are onium salts and do not have any local anaesthetic potency, there is no reason to expect a procaine-like action. Since the block is completely reversible, there is no reason to suspect any action such as that due to botulinus toxin. Finally, the possibility that acetylcholine liberation might be depressed was tested directly in one experiment, in which the tibialis anterior muscle of a cat was dissected and perfused in isolation with eserinized a direct consequence of this anticholinesterase activity or not. . Cat, chloralose, 2.6 kg. Tibialis; nerve shocks every 10 sec. At arrow, 26 μg. C10 injected intravenously. The same dose was given 5 min. previously without any effect. It is well known (Briscoe, 1936; Rosenblueth, Lindsley, and Morison, 1936) that eserine and other anticholinesterases can cause neuromuscular block, which has been ascribed to the presence of an excess of acetylcholine in the region of the neuromuscular junction. Under such conditions, however, the interposition of a tetanus, or the close arterial injection of acetylcholine increases the block for the succeeding twitches (Bacq and Brown, 1937). We have used this phenomenon as a test of the nature of the block caused by C10. Figs. 1a and 4 show that there is no such depressant action by a tetanus or by injection of acetylcholine respectively on the twitch of a muscle partially paralysed with C10; and it has been our constant experience that it would be hard to judge from the subsequent twitches that a tetanus had been applied or an injection made. (An apparent slight deepening of the block by acetylcholine in Fig. 9 was due to traces of C10 from the previous injection.) We have, moreover, never observed any relation between the rate of stimulation and the development of the block. Indeed, with a large dose of C10 almost complete paralysis may occur after a single twitch. It is unlikely, therefore, that block due to C10 is the result of the accumulation of acetylcholine at the end-plate. We do not wish, however, to underestimate the resemblance of some of our tracings to those resulting from injections of potent antiesterases (cf. Brown, Burns, and Feldberg, 1948), but it is possible that some of the latter produce a block otherwise than by their antiesterase action. Our experiments in this connexion also showed that a muscle could still maintain a tetanic contraction at a height comparable with the twitch tension when partially paralysed with C10. It is well known that the curarized muscle cannot do this; our experiments on this important difference will be reported separately. In the anaesthetized cat, the complete or nearly complete paralysis of tibialis that follows an intravenous dose of 30 μg./kg. of C10 usually begins to recover in 5–10 min., and recovery is complete in about 15 min. Sometimes a twitch tension greater than the initial may be observed for a few minutes of the recovery (recapitulating the initial potentiation) before it returns to the original level. The presence of the drug, however, is still detectable for some time after the twitch tension has returned to normal, since the same dose given again less than 30 min. after the first injection produces a greater effect. But with suitable spacing of doses, reproducible cycles of paralysis and complete recovery can be obtained for many hours, the only important change commonly observed being a diminution of the initial potentiation with the lapse of time. Our experience also suggests that C10 has a rather steep dose-response curve; thus, a dose of 20 μg./kg. was sometimes without visible effect on twitch tension in an animal in which 30 μg./kg. produced temporarily a complete block. Corresponding to this, recovery from a C10 block, once it starts, is often rather rapid. d-Tubocurarine chloride differs significantly both in having a longer duration of action for a given peak action and in the slower waning of its effects. Similar time relations are observed in unanaesthetized cats and in rabbits; both animals, after a dose of C10 sufficient to paralyse them fully, recover in about 10 min., whereas d-tubocurarine chloride has a somewhat more prolonged action. In the monkey, however, the reverse is the case, and with equally effective doses C10 has a duration of action about two to three times longer than that of d-tubocurarine chloride. We have given C10 by other routes in a few experiments. Administered by stomach tube, C10 is ineffective in cat and rabbit in doses less than fifty times the effective intravenous dose, but a dose of a hundred times may be lethal in an animal starved for 24 hours. The paralysis takes an hour or more to appear. By the subcutaneous route in the rabbit, about three times the intravenous dose is required for equal maximum effects, and the paralysis does not appear for about 10 min. nor disappear entirely for about 2 hours. With intramuscular injections, slightly smaller doses are required, and the onset of paralysis is quicker. We have not, however, studied the relative doses required for equal peak effects by the various routes in any detail, and the values quoted are only approximate. Fig. 6a is the record of an experiment in which the respiratory volume was recorded simultaneously with the response of the tibialis muscle to single nerve shocks. Although the muscle response was almost completely abolished, the respiratory volume was but slightly affected. This has been a constant and striking experience. Sometimes, indeed, an increase in the respiratory minute volume has been observed; a counterpart, perhaps, of the phase of potentiation of the muscle twitch which has been already mentioned. With larger doses of C10, respiratory depression can of course be induced; but it is again remarkable how much sooner recovery of adequate respiration takes place than recovery of the normal muscle twitch. . Cat, chloralose. Record of respiration and of tibialis; nerve shocks every 10 sec. (a) At arrow, 0.1 mg. C10 intravenously. (b) At arrow, 0.2 mg. d-tubocurarine chloride intravenously. In Fig. 6b is also shown the record of a similar experiment with d-tubocurarine chloride. In contrast to C10, distinct respiratory depression was produced, with an almost negligible effect on the tibialis twitch. Our experience has been consistently of this kind, that with d-tubocurarine chloride, respiratory depression accompanies or even precedes paralysis of the tibialis twitch. The contrast between the two drugs in this respect appeared so striking that it will be reported more fully elsewhere. Although most of our experiments were made with cats anaesthetized with chloralose, we have also used ether alone and pentothal alone. In the one experiment with pentothal anaesthesia, C10 appeared to be somewhat more effective than with chloralose, 20 μg./kg. being adequate for complete abolition of the tibialis twitch, although respiration was only slightly depressed with the above dose. No preliminary potentiation or fasciculations were seen. With ether (6–7 per cent), on the other hand, C10 was less effective than with chloralose, and the fully paralysing dose of C10 varied from 40 to 70 μg./kg. in four animals. Potentiation of the twitch and fasciculations were never seen, even with only feebly paralysing doses. Sparing of respiration was much less prominent than in the animal anaesthetized with chloralose. Tetani were sustained very poorly, as with d-tubocurarine chloride. Indeed, the effects of ether could be said to resemble rather closely those of a previous dose of d-tubocurarine chloride, which are described below. Attempts to estimate the potency of these compounds led at once to the discovery of a very great variation with different species. For the bulk of the experiments different methods of testing were used with different species. Fig. 7 summarizes the results, which are shown in more detail in Table I, together with corresponding figures for d-tubocurarine chloride. Further experiments on a few of the compounds showed, however, that variation in the method of testing accounted for only a small part of the species difference. We took as a standard that dose (RD50) which, after injection rapidly by the intravenous route into unanaesthetized animals, causes loss of the ability to right themselves in half the animals. In cats this was very close to the dose required to reduce the twitch tension of tibialis by 95 per cent in the animal anaesthetized with chloralose; in rabbits, it was about 20 per cent less than the head-drop dose (HDD), and it was about 20 per cent less than the LD50 in mice and rats. The figures for monkey were direct estimates of RD50: those for man are based on some preliminary trials (Organe, Paton, and Zaimis, 1949) and represent the dose that made the subjects too weak to sit up or stand or lift any of their limbs. If the activity of C10 in the various species is corrected to this standard, comparable estimates of its potency in these species are obtained, and are shown in Table II. The results of tests on frogs are also included, but it must be remembered that the route of injection used (ventral lymph sac) was quite different from that in the other species. . Variation of potency of bistrimethylammonium compounds, with varying length of polymethylene chain, and of d-tubocurarine chloride, among different species. Abscissa: number of carbon atoms in chain. Ordinate: dose in mg./kg. (Extrapolation of the curves beyond C12 to C18 has not been attempted.) The actions of these drugs on various species also differed in the manner of the paralysis, and several interesting points emerged. In the monkey, the earliest sign of weakness was an inability to keep the arm above the head; after this appeared progressive weakness of movement and dropping of the head, and only with deep paralysis was the ability to sit up lost. In cats, the paralysis progressed more uniformly, and neck, trunk, and limbs seemed to weaken together; but an unusual and constant feature was the complete relaxation of the nictitating membrane for so long as the paralysis lasted: this relaxation is, indeed, the first sign of paralysis observed after an intravenous injection. Finally, in rabbits, weakness of the hindlegs appeared first, while further paralysis of the limbs and head-drop followed. The opportunity was taken of administering C10 to one baboon (Papio anubis), weight 14.5 kg., which was suffering from a traumatic paraplegia and was to be killed. After the slow injection of C10 at a rate of 0.5 mg./min., head-drop occurred after 2 mg. had been injected, followed by almost complete skeletal paralysis; respiration was still adequate although depressed. Injection of 50 mg. of C5 9 min. later caused partial recovery of arm strength and deepening of respiration. Despite the species variation, C10 was the most potent member of the series by any test for neuromuscular block. Its immediate neighbours in general closely resembled it qualitatively, although not in potency. The steepness of the curve relating potency to chain-length deserves comment; for instance, shortening the polymethylene chain from eight to seven carbon atoms reduced potency more than tenfold. Members of the series remote from C10, however, gave the impression that new activities were appearing. The abrupt change of slope in Fig. 7 in the region of C6 and the attenuation of the species difference with C18 are of great interest. Since head-drop and lethality are not specific tests for neuromuscular block, it is possible that the other pharmacological actions of the series described below become prominent in bringing about an end-point with the members of the series which are relatively inactive in causing neuromuscular block. A point of interest lies in the activity of tetramethylammonium iodide relative to these compounds. A dose of 5 mg./kg. injected intravenously into a cat produced an effect on tibialis twitch comparable with that of 30–40 μg./kg. of C10. This potency, although small, is greater than that of C4, C5, and C6, which fail to depress neuromuscular transmission in doses of 40 mg./kg. Our results with mice, rats, and rabbits indicate that C2 and C3 are equally or even more inactive in this respect. Our first attempts to compare the potencies of these two drugs on the cat's tibialis yielded puzzling results, until it was realized that C10 was less effective than usual when d-tubocurarine chloride had been given previously. Fig. 1a and 1b illustrates this point on cat's tibialis. It can also be shown on the rabbit head-drop, and a typical experiment is cited in Table III. In this experiment the preliminary dose of curare was such as caused distinct (although transient) weakness of the animals; nevertheless, a larger dose of C10 was required subsequently to produce head-drop. The previous administration of C10 does not (despite its feeble anticholinesterase action) lessen the effect of d-tubocurarine chloride, but rather augments it to a slight degree according to the interval between the injections (Table IV). This antagonistic effect of d-tubocurarine chloride is detectable in the rabbit for an hour and in the cat may persist for a similar period. The duration of the antagonism and its effectiveness become greater as the dose is increased. In addition, the fasciculations and potentiation normally produced by C10 are uniformly abolished. These actions are not specific to d-tubocurarine chloride; we have observed them also with its methyl ether, d-bebeerine methiodide, N-methyldiaboline iodide, and with tri(diethylaminoethoxy)-benzene triethiodide (“Flaxedil”). Eserine and neostigmine are without effect on the neuromuscular paralysis due to C10 and its neighbours. Fig. 2 exemplifies the failure of neostigmine to reverse such block in the tibialis muscle; Fig. 8b is an illustration of an effective antagonism by a similar dose to d-tubocurarine chloride. (The slight deepening of block due to C10 by prostigmine in this experiment (Fig. 2) was seen at other times, but not constantly.) Eserine was equally ineffective. Similarly with the rabbit head-drop test, a dose of 0.05 mg. neostigmine methyl sulphate per kg., previously given, which increased the HDD of d-tubocurarine chloride from 0.316 mg./kg. to 0.615 mg./kg. in four rabbits, did not alter the HDD dose of C10 significantly from 0.149 mg./kg. (Table V). . (a) Cat, chloralose, 2.2 kg. Tibialis: nerve shocks every 10 sec At (1), 0.1 mg.C10i.v. At (2), 10 mg.C5 i.v. (b) Cat, chloralose, 2.8 kg. Tibialis: nerve shocks every 10 sec. At (1), (2), (3), 1 mg., 0.5 mg., 0.5 mg., respectively, d-tubocurarine chloride i.v. At (4), 0.5 mg. neostigmine i.v. Observations on the frog's rectus, in which C10 produces a contracture, showed that lower members of the series, inactive both in causing neuromuscular block and in producing a contracture, antagonized this action of C10: C5 and C6 were particularly effective in this respect. This suggested that such antagonism might also exist at the mammalian neuromuscular junction. Fig. 8, a record of an experiment to test the point on the cat's tibialis with C5, shows that this expectation was fulfilled. Table VI summarizes the results of a similar experiment with C6 using the rabbit head-drop method. Table VI also shows that C6 not only has no antagonistic action to d-tubocurarine chloride but may even potentiate its action somewhat. The antagonistic action of C5 (and C6) is complicated to some extent by their ganglionic action (described below), and with large doses there is no doubt that a fall of blood pressure occurs which is due to paralysis of sympathetic vascular tone. This does not, however, affect the recovery of neuromuscular transmission when C5 is administered during a paralysis due to C10. A useful antidotal action can be observed in rabbit and monkey where the dose of C5 is only ten times that of the paralysing dose of C10, and under these conditions vascular effects are trivial. With this ratio of doses, shallow paralyses are cut short, recovery from deeper paralyses is accelerated, and respiratory depression due to larger doses still is greatly lessened. On the cat tibialis preparation, however, a larger ratio of C5 to C10 is usually required, and 3 mg./kg. C5 may be required for a prompt antagonism. The antagonistic action of C5 is easily reversed by increasing the dose of C10, and the renewed onset of neuromuscular block can be again antagonized by further doses of C5; there is a limit to this process, however, and with very large doses of C5 little more recovery from neuromuscular block can be obtained. Similarly, after large doses of C10 it is difficult to demonstrate any antagonism (just as neostigmine is not very effective after large doses of curare). Potassium has been shown to antagonize the neuromuscular block due to curare (Wilson and Wright, 1936). We have therefore tested it against a similar block due to C10 (Fig. 9b). It will be seen that there is no important action, although the dose is enough (when given to the unparalysed muscle) to produce a typical potentiation of the twitch (Fig. 9a). Adrenaline appears to be equally ineffective. A few seconds after the injection of 10 mg. of C6 into a rabbit, we observed that its ears flushed vigorously and became warm, and we have already mentioned the ability of C5 and C6 to cause a fall of blood pressure. The analysis of these effects revealed that these compounds paralyse autonomic ganglia. The evidence for this will be presented in another paper. For the present we wish only to describe the experiments made to compare quantitatively the potencies of C6 and its neighbours in this respect. The cat's nictitating membrane, excited to a sustained contraction by stimulation of the preganglionic cervical sympathetic trunk at a frequency of 10 shocks per second, provided a useful test for activity of these compounds on transmission in the superior cervical ganglion. Fig. 10 shows a typical tracing in which C5 and C6 and tetraethylammonium iodide were compared. Table VII gives a summary of those doses of these compounds and of tetraethylammonium iodide which caused roughly equal peak relaxations of the nictitating membrane. There was a considerable difference between C5 and C6 and tetraethylammonium iodide in their duration of action, the former two drugs acting more slowly and exerting their action three to four times as long as the latter, for doses which gave equal peak effects. . Cat, chloralose. Record of sustained contraction of nictitating membrane excited by stimulation of cervical sympathetic 10 sec. intravenous injections. Effects of 0.2 mg. C6; 0.25 mg. C5; and 3.5 mg. tetraethylammonium iodide (T.E.A.). To test the effect on parasympathetic autonomic ganglia, we used the technique of Trendelenburg described by Feldberg and Lin (1949). Fig. 11 shows typical tracings, and Table VII gives the relative potencies of the compounds tested. It was again observed by comparing the ease with which they could be washed out that C5 and C6 were more persistent in their action than tetraethylammonium iodine. . Isolated rabbit intestine. Record of length (upper tracing) and volume (lower tracing); intestine stimulated by rapid rise of intra-intestinal pressure of 3 cm. water. (a) 1, normal response. 2, 0.1 mg. C6 added to bath. 3, 0.2 mg. C6. 4, 15 μg., and 5, 30 μg. d-tubocurarine chloride. 6, normal res" @default.
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W2028263839 title "THE PHARMACOLOGICAL ACTIONS OF POLYMETHYLENE BISTRIMETHYLAMMONIUM SALTS" @default.
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