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© 1987 Oxford University Press

research-article

Alterations of High-Energy Phosphate Compounds in the Skeletal Muscles of Rats Intoxicated with Diisopropylphosphorofluoridate (DFP) and Soman

RAMESH C. GUPTA and WOLF-D. DETTBARN1

Department of Pharmacology and The Jerry Lewis Neuromuscular Disease Research Center, School of Medicine, Vanderbilt University Nashville, Tennessee 37232

Alterations of High-Energy Phosphate Compounds in the Skeletal Muscles of Rats Intoxicated with Diisopropylphosphorofluoridate (DFP) and Soman. GUPTA, R. C, and DETTBARN, W.-D. Fundam. Appl. Toxicol. 8, 400–407. The purpose of the present investigation was to determine the changes in high-energy phosphate compounds and to establish their relationship with organophosphate-induced necrotic lesions in skeletal muscles of rats. Following an acute toxicity signs-producing dose of either diisopropylphosphorofluoridate (DFP) (1.5 mg/kg, sc) or soman (0.1 mg/kg, sc), a significant decline in phosphocreatine (PC) was seen as early as within 1 hr, coinciding with the appearance of necrotic lesions, as reported earlier. The maximum decrease in PC was measured after 6 hr. At this time, among the muscles studied, the hemi-diaphragm (the muscle which is known to show the greatest number of necrotic lesions with both of the organophosphorus compounds) showed maximum decrease in PC (57%) with soman treatment. A detailed analysis of adenine nucleotides indicated a significant decrease of adenosine triphosphate (ATP) in all three skeletal muscles, with a marked increase in adenosine monophosphate (AMP) and adenosine diphosphate (except in extensor digitorum longus (EDL)). The levels of creatine in all three skeletal muscles remained unaltered throughout the time-course of study. The observed changes in PC, ATP, and AMP were reversed toward control baseline values after 72 hr. Daily administration of DFP (0.5 mg/kg, sc/day) for 14 days caused only a significant decrease of PC in EDL and soleus during the toxic phase (Day 5), with recovery toward the normal value during the tolerance phase (Day 14). It is concluded that both DFP and soman reduced the PC in skeletal muscles, and the time-course for PC reduction correlates well with the previously reported time-course for muscle fiber necrosis. It is suggested that the reduction in PC is caused through an increased demand to meet ATP requirements during severe muscular fasciculations.


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