TWITCH POTENTIATION OF SKELETAL-MUSCLE BY PHYSOSTIGMINE AT DIFFERENT PH

  • 1 January 1976
    • journal article
    • research article
    • Vol. 197  (2) , 439-451
Abstract
Earlier research, done with external media at pH 7.2 was extended with studies at pH 6.4, 8.4 and 7.2, to determine the roles of protonated and neutral forms of physostigmine (a weak base with pKa = 8.2) in causing twitch potentiation of frog [Rana pipiens] sartorius muscle. Physostigmine, especially at relatively high pH (8.4) and concentration (1.5 mM), blocks excitation. Physostigmine potentiation increases with pH, as the still active fibers in even a heavily blocked muscle show increased peak contraction time, indicating that potentiation is occurring in terms of prolongation of the active state. At pH 6.4 and 8.4, 1 mM physostigmine causes no change in the mechanical threshold of K depolarization contractures of toe muscles, as found previously at pH 7.2. Physostigmine increasingly prolongs the action potential as pH rises, i.e., in positive correlation with the twitch potentiation, indicating that this electrical change is the prime determinant of the potentiation. Physostigmine decreases the overshoot in proportion to increase in pH, suggesting that the overshoot is not critically needed for full excitation-concentration coupling but serves as a safety factor. The increase of various potentiation parameters with increasing pH indicates that potentiation is proportional to the concentration of the external, permeant, uncharged physostigmine. The related, but impermeant, neostigmine and acetylcholine produce no potentiation (nor, essentially, and other significant mechanical effects). Permeant diisopropylfluorophosphate (DFP) potentiates the twitch in all electrical and mechanical respects as physostigmine does. Physostigmine probably acts by 1st penetrating the fibers as the permeant B, which then, because of the internal pH of 6.8, is transformed into relatively large concentrations of BH+. Since DFP will be internally located as well as the internal BH+, and since both are potent antiacetylcholinesterases, possibly the common effects of DFP and physostigmine on the action potential, and thus on the twitch, are caused by their inhibition of the plasma membrane esterase. In contrast to their general influence as twitch potentiators, physostigmine and DFP inexplicably reduce the depth of the latency relaxation.

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