SUMMARY.Tacrine and tuniphenazole increase the excitability of the electrically-stimulated ilemn and restore excitability after depression by morphine. These effects are accompanied by inhibition of cholinesterase. Neither drug prevents the inhibitory action of morphine on acetylcholine release; hence it is concluded that the interaction of morphine and amiphenazole or tacrine on the electrically-stimulated ileum is non-specific, and in the case of tacrine, results from its effects on cholinesterase.The evidence that the excitatory action of amiphenazole on the ileum is a consequence of its action on cholinesterase is less clear. The drug does not increase sensitivity to acetylcholine, and instead depresses its output. Although tacrine also depresses the output of acetylcholine the effect is seen only in concentrations approximately one thousandfold greater than those producing equivalent inhibition of cholinesterase.Attention is drawn to the kinetics of inhibition of cholinesterase by tacrine as a factor which may influence its physiological actions.INTRODUCTION.
Diabetes mellitus can lead to neuropathy of enteric neurons, resulting in abnormal gut motility. These studies investigated voltage-dependent contributions of muscarinic M₃ receptor activation by acetylcholine and neurokinin NK₁ receptor activation by neurokinins to nerve-stimulated contractions of longitudinal ileal strips from STZ guinea-pigs, a type 1 diabetic model with insulin deficiency, but mild hyperglycaemia. Contractions to bethanechol, substance P methyl ester, and nerve stimulation were greater in diabetic as compared to control ileum. The muscarinic M₃ receptor antagonist 4-DAMP at lower voltages and the neurokinin NK₁ receptor antagonist SR140333 at higher voltages, but not the neurokinin NK₁ receptor antagonist CP-96,345, were more effective at inhibiting nerve-stimulated immediate peak contractions and total areas of contraction of ileum from diabetic as compared to control animals. For diabetic ileum, voltage-dependent increases in the areas of nerve-stimulated contraction were observed in the presence of 4-DAMP and CP-96,345 but not SR140333. At low voltages only, nerve-stimulated release of acetylcholine was greater from diabetic as compared to control ileum. Fluorescence intensity of tachykinin-like immunoreactivity was increased in ileal myenteric ganglia from diabetic as compared to control animals. In diabetic guinea-pigs, stronger ileal nerve-stimulated contractions reflected increased release of acetylcholine at lower voltages and tachykinins at higher voltages, as well as increased sensitivity of smooth muscle M₃ and NK₁ receptors to acetylcholine and tachykinins. Hypoinsulinaemia may be a primary contributor to intestinal motility dysfunction in type 1 diabetes mellitus.
Morphine depresses the resting output of acetylcholine (Ach) in the guinea-pig ileum (Schaumann, 1957) and also the raised output following electrical stimulation (Paton, 1957). Since the latter effect is consistent with a site of action of morphine on postganglionic cholinergic nerves in the intestine (Paton, 1957(Paton, , 1963, the question arises whether effects of the drug on Ach release in the resting intestine may also be attributed to inhibition of nervous structures. This possibility is supported by Johnson's (1963) finding that the resting output of Ach in the guifea-pig intestine is reduced by as much as 85% by procedures which are likely to depress nervous activity, including incubation with cocaine (5 Jug/ml.), procaine (10 ug/ml.), hemicholinium, lowered calcium, raised magnesium, and cooling to 250 C. In the present study we have sought further information of the site of action of morphine in the resting intestine by examining its inhibitory effect under a variety of conditions which modify nerve transmission and/or neurotransmitter release. METHODSThe resting output of acetylcholine in the guinea-pig intestine has been measured under two experimental conditions:The first procedure (a) was that of Schaumann, in which small segments of intestine, closed by ligatures at both ends, were randomly distributed among a number of incubating flasks containing magnesium-free Tyrode solution gassed with 95% oxygen, 5% carbon dioxide.The magnesium-free Tyrode solution was of the following composition: NaCl 138 mM, KC1 2.7 mM, CaCl2 1.8 mM, NaHCO3 12.0 mM, NaH2PO4 3.5 mM, glucose 5.5 mM.In experiments where sodium ion concentration was reduced the osmotic pressure of the solution was adjusted by adding the appropriate amounts of sucrose. Incubation was carried out in a shaking bath at 370 C and the incubation fluid was removed periodically for bioassay; physostigmine (10-5M) was present throughout.The second procedure (b) was designed to allow removal of intraluminal contents, which may accumulate over long periods of incubation and possibly interfere with the generation of acetylcholine.A 10-cm portion of the intestine was drawn over a perforated polythene tube (diameter 3 mm) and ligated at each end as shown in Fig. 1
Tacrine is an inhibitor of cholinesterase comparable in potency with physostigmine. Its clinical applications include antagonism of curare (Gershon & Shaw, 1958), potentation of suxamethonium-induced relaxation of skeletal muscle (McCaul & Robinson, 1962), and antagonism of the sedative action of morphine (Stone, Moon & Shaw, 1961). The last property is relatively novel and is not displayed by all inhibitors of cholinesterase (Shaw & Bentley, 1953, 1955. For this reason, we have analysed the actions of tacrine on smooth and slow-contracting muscle in greater detail to assess whether these actions can be accounted for solely by inhibition of cholinesterase. The results with smooth muscle have been presented separately (de la Lande & Porter, 1963); the present report is confined to the comparison of the actions of tacrine and of potent anticholinesterases on the isolated rectus abdominus muscle of the toad and on the semispinalis muscle of the chicken (Child & Zaimis, 1960). METHODSThe rectus abdominus muscle preparation of the toad (Bufo Marinus) Paired muscles were set up separately in 5-ml. organ-baths containing (g in 1 1. of distilled water): NaCl 6.7, KCl 0.24, CaCl 0.14, MgCl2 0.20, NaHCO3 1.68, NaH2PO4 0.49 and glucose 3.0. Drugs to be added to the preparation were made up in the same solution. The solutions were gassed with oxygen at room temperature (16 to 250 C).The responses of the muscle to a drug were examined by replacing the above solution with the solution containing the drug and recording the contraction on a smoked drum by means of an isotonic lever (magnification x 7, tension 1.5 g). The height of the contraction after a fixed interval of time (1.5 to 2 min) was recorded, after which the organ-bath was drained; the tension of the preparation was restored to the resting value by means of a weight or an electromagnet. After recording responses for different concentrations of the stimulant being investigated, the anticholinesterase was added to the reservoir of the solution bathing one of the preparations, and further measurements were made of the responses of both preparations to the stimulant. The only departure from this procedure was with tetraethyl pyrophosphate when the method of Hobbiger (1950) was used; the drug was added for an initial period of 45 min in a concentration of 1.5 x 10-6 M to the bathing solution and replenished at intervals of 15 min.The change in sensitivity of the muscle to acetylcholine was assessed as follows: maximum responses (R) to acetylcholine were obtained, and the concentration (C,) of acetylcholine which produced a response of one-half this magnitude (R/2) in 90 sec was measured or estimated from a dose/response curve. The muscle was then treated with an anticholinesterase and the concentration of acetylcholine (C,) required to produce the former response (R/2) again estimated. When comparisons were made between acetylcholine and other stimulants, the concentrations of the latter were adjusted to provide contractions of approximately equal magnitude to that by a...
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