Functional evaluation of acute vincristine toxicity in rat skeletal muscle.
Vincristine sulfate (VCR) was administered intravenously to rats at doses of 0.25, 0.5, and 0.75 mg/kg. During the first week following VCR treatment, extensor digitorum longus (EDL) muscle contraction strength and fiber electrophysiologic parameters were measured. At all doses tested, VCR strongly reduced twitch and tetanic tension. EDL fiber resting membrane potential was affected in a dose-dependent manner, and membrane depolarization was associated with the loss of excitability. Local membrane hyperpolarization by intracellular current application restored the capacity to produce action potential (AP). However, to elicit APs with a normal rate of rise, polarizing current had to be maintained for 3-5 minutes, indicating that the removal of Na+ channel inactivation followed a slow kinetics. Minor alterations in spontaneous synaptic transmission and in evoked transmission during high-frequency repetitive stimulation were seen only at the highest dose. It is suggested that VCR impairs skeletal muscle function by affecting primarily the contractile apparatus, whereas sarcolemmal alterations are evident at increased doses of the drug.
Di Gregorio
F
F
Department of Peripheral Nervous System Research, Fidia Research Laboratories, Abano Terme, Italy.
Favaro
G
G
Fiori
M G
MG
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012508:Sarcolemma / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects; D014750:Vincristine / Q000633:toxicity*
D015222:Sodium Channels; D014750:Vincristine