ABNORMAL PHARMACOLOGICAL RESPONSES OF ISOLATED NERVE-MUSCLE PREPARATIONS FROM MUSCULAR DYSTROPHIC MICE

¹ Radioisotope Service, Veterans Administration Center, and the Departments of Physiological Chemistry and Surgery/Anesthesia, University of California Medical Center, Los Angeles, California

Earlier in vivo studies of Bar Harbor strain 129 mice having a hereditary disease, dystrophia muscularis, showed them to be supersensitive to neostigmine and less sensitive to d-tubocurarine (d-TC) when compared to litter-mates without the disease. By testing the pharmacological responses of suitable nerve-muscle preparations isolated from dystrophic and nondystrophic mice of this strain it has now been possible to establish the peripheral nature of this abnormal response to these compounds. First, it is shown that the peroneus longus muscle is supersensitive to neostigmine. The latter at a concentration of 0.02 µg/ml caused rapid, spontaneous twitching in all dystrophic peronei but produced only an occasional twitch in the peronei fromu normal litter-mates. Even five times this concentration failed to produce such violent twitching in the normal preparations. Increased contractile tension and spontaneous twitching were antagonized (a) by concentrations of d-TC below those which effected a neuromuscular block or (b) by increased concentration of neostigmine. Second, it was found that the hemidiaphragm, and, to a greater extent, the peroneus muscles were resistant to d-TC. Thus a 50% neuromuscular block was produced in the normal mouse diaphragmphrenic nerve preparation by an average of 0.73 µg of d-TC/ml, but it required 0.86 µg/ml to produce the same effect in the diaphragm isolated from dystrophic mice. Similarly, a 50% neuromuscular block was obtained in the normal peroneus longus muscle with 0.22 µg of d-TC/ml but with 0.45 µg/ml in the dystrophic peroneus. In contrast to the relative resistance of dystrophic muscle to the paralyzing effect of d-TC, these muscles appeared to be more sensitive to the second phase of a paralysis induced by decamethonium (C-10) than muscles from litter-mate controls.