mercaptopurine and Muscular-Dystrophy--Animal

6-Mercaptopurine (6-MP) was injected daily (2 mg/kg sc) into 24 Sprague-Dawley rats during the first three weeks of life. There were 23 saline-injected control animals. Atrophy of the muscles of the hindquarters in the 6-MP-treated rats began at about 4 months of age. The membrane potentials (Em) of the isolated extensor digitorum longus (EDL) and the caudofemoralis (CF) muscle (in situ) were measured with intracellular microelectrodes at 6-18 months of age. It was found that there was a wide spectrum of fibers with respect to electrical abnormalities in the 6-MP-treated muscles, some fibers having perfectly normal parameters. However, the mean resting Em of fibers in the EDL muscle of 6-MP-treated rats (-61.1 +/- 0.7 mV) was lower than that of the control rats (-69.7 +/- 0.6 mV). The same was true for the fibers of the CF muscle (-64.9 +/- 1.5 mV for 6-MP-treated fibers vs -71.6 +/- 1.3 mV for controls). Experiments done in the presence and absence of ouabain indicated that the contribution of the electrogenic pump potential to Em was similar in 6-MP-treated and control rats, and therefore could not account for the depolarization observed in 6-MP-treated rats. The data also demonstrated that this depolarization was not due to a decreased intracellular K+ concentration. The Na+/K+ permeability ratio (PNa/PK) was higher in the 6-MP-treated rats, and could account for the decreased resting Em. The APs of 6-MP-treated rats (elicited from the natural Em of the fiber) had more fibers with a lower maximum rate of rise (+Vmax) (330 +/- 20 vs 391 +/- 17 V/sec) and lower amplitude (65.1 +/- 2.9 vs 73.3 +/- 1.8 mV) than in the control muscles. When hyperpolarized to -90 mV before eliciting the AP, fibers from 6-MP-treated rats still displayed depressed AP rates of rise (+Vmax of 382 +/- 19 vs 511 +/- 21 V/sec in controls), depressed AP amplitudes (97 +/- 2.1 vs 105 +/- 1.6 mV in controls) and slightly prolonged duration at 50% amplitude (APD50) (0.66 +/- 0.03 vs 0.60 +/- 0.02 sec in controls). These electrophysiological alterations produced by this chemically-induced myopathy are similar to those observed in murine muscular dystrophy.

Topics: Action Potentials; Animals; Animals, Newborn; Membrane Potentials; Mercaptopurine; Muscles; Muscular Dystrophy, Animal; Ouabain; Permeability; Potassium; Rats; Rats, Inbred Strains