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Volume 17, Number 11, Issue of June 1, 1997 pp. 4500-4507
Copyright ©1997 Society for Neuroscience

Effects of 4-Aminopyridine on Muscle and Motor Unit Force in Canine Motor Neuron Disease

Received Jan. 10, 1997; revised March 17, 1997; accepted March 21, 1997.

M. J. Pinter¹, R. F. Waldeck¹, T. C. Cope², and L. C. Cork³

¹ Department of Neurobiology and Anatomy, Allegheny University, Philadelphia, Pennsylvania 19129, ² Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322, and ³ Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California 94305-5410.

Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal dominant disorder of motor neurons that shares features with human motor neuron disease. In animals exhibiting the accelerated phenotype (homozygotes), we demonstrated previously that many motor units exhibit functional deficits that likely reflect underlying deficits in neurotrans-mission. The drug 4-aminopyridine (4AP) blocks voltage-dependent potassium conductances and is capable of increasing neurotransmission by overcoming axonal conduction block or by increasing transmitter release. In this study, we determined whether and to what extent 4AP could enhance muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increased nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, symptomless HCSMA animals or in one younger homozygous animal. The possibility that this difference was caused by the presence of failing motor units in the muscles from homozygotes was tested directly by administering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units could be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA animal. The ability of 4AP to increase force in failing units may be related to the extent of failure. Although 4AP increased peak forces during unit tetanic activation, tetanic force failure was not eliminated. These results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP action are considered.

Key words: neuromuscular disease; synaptic transmission; transmitter release; muscle force; potassium channel; calcium influx

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