Theophylline, epinephrine, and neostigmine facilitation of neuromuscular transmission.

Epinephrine can enhance transmission under certain conditions in both the central and peripheral portions of the nervous system.'-6 Increased quantities of acetylcholine are released in response to epinephrine at ganglionic and neuromuscular junctions.4, s At the biochemical level, epinephrine stimulates the formation of adenosine 3',5'-phosphate (cyclic AMP) by preparations of many tissues, and in a few instances increased intracellular concentrations of cyclic AMP have been shown to result from the application of the hormone to tissue. Cyclic AMIP levels also can be raised by theophylline, which inhibits hydrolysis of the nucleotide by a phosphodiesterase. These and other observations have led to the concept that cyclic AMP is the mediator of several epinephrine actions.7 The possibility that the effects of epinephrine within the nervous system might also be mediated by cyclic AMP led to the present experiments. These have shown that theophylline is capable of potentiating the effects of epinephrine on sciaticgastrocnemius preparations of the cat. This potentiation is blocked by propranolol, a f3-adrenergic blocking agent, and does not occur in the curarized preparation. Methods.-Cats of about 2 kg weight were anesthetized with ether, then injected intravenously with chloralose, 80 mg/kg; pentobarbital sodium, 6 mg/kg; and atropine sulphate, 1 mg/kg. The trachea was intubated and the adrenals tied off. Blood pressure was recorded by means of a mercury manometer connected to a carotid artery cannula. Supramaximal stimuli (1 msec duration, 6/min) were delivered without interruption from a Grass S4E stimulator through shielded electrodes to the distal portion of the divided sciatic nerve. A hole (3 mm diameter) was drilled through the lower end of the femur, which was then fixed by means of a steel rod. The Achilles tendon was freed and connected to a tension lever. Single shocks elicited an increase in tension of 1.5 to 2.0 kg. The muscle was stimulated directly in curarized preparations by stimuli (1 msec duration, 6/min) passed between the steel rod fixing the femur and a platinum wire in the Achilles tendon. Amounts of L-epinephrine bitartrate and of neostigmine bromide which were given are recorded in terms of the salts. Values for theophylline (as a solution in warm 50 mM sodium acetate, pH 7.2, or as aminophylline) are expressed in terms of the base. Propranolol (Inderal) was obtained from Imperial Chemical Industries, and d-tubocurarine was kindly supplied by Burroughs, Wellcome and Co. All drugs were administered intravenously. Results.-Neostigmine was used in these experiments because epinephrine consistently causes a greater increase in contractions of nerve-muscle preparations when an anticholinesterase is also present.2 Neostigmine was usually given three times at intervals of 20 minutes before an increase in tension was observed. There-