POTENTIAL RISK OF MYOPATHY BY HMG-COA REDUCTASE INHIBITORS - A COMPARISON OF PRAVASTATIN AND SIMVASTATIN EFFECTS ON MEMBRANE ELECTRICAL-PROPERTIES OF RAT SKELETAL-MUSCLE

To get insight into the potential risk of myopathy associated with the rapy involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibit ors, we evaluated in vivo and in vitro the effects of a daily 2 to 3-m onth treatment with pravastatin (100 mg/kg) and with simvastatin (5, 1 0 and 50 mg/kg) on the electrical properties of rat skeletal muscle fi bers. The electromyographic activity revealed no sign of myopathy duri ng treatment with pravastatin and with simvastatin. At the end of the treatment, the passive and active membrane electrical parameters of th e extensor digitorum longus muscles were measured in vitro by computer ized two-intracellular-microelectrode technique. A dose-dependent redu ction of membrane chloride conductance was recorded in extensor digito rum longus fibers of simvastatin-treated groups, and at 50 mg/kg the r eduction of chloride conductance was significant in 6 out of the 7 tre ated rats, By contrast, none of the pravastatin-treated rats showed si gnificant alteration of chloride conductance. Consequently, the excita bility parameters were modified by simvastatin but not by pravastatin treatment, whereas the resting membrane potential was not affected, An increase in potassium conductance, reduced by in vitro application of glybenclamide, was recorded in 30% of the simvastatin-treated rats (5 0 mg/kg) and in only 15% of the pravastatin-treated rats, Our results suggest that the risk of myopathy is much higher with the lipophilic s imvastatin than with the hydrophilic pravastatin and support the hypot hesis that the muscle toxicity of HMG-CoA reductase inhibitors is due to an intracellular action mediated by the inhibition of muscle choles terol synthesis.