Some Actions of Tacrine on Slow Muscles of the Toad (Bufo Marinus) and the Chick

Abstract

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...