Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 332, Issue 3, pp 230–235 | Cite as

Endplate channel actions of a hemicholinium-3 analog, DMAE

  • Karim A. Alkadhi
Original Articles

Summary

The effect of the hemicholium-3 analog, DMAE, on endplate currents (EPC) was investigated in the transected cutaneous pectoris muscle of the frog using a conventional two-microelectrode voltage clamp. At a low concentration (5 μM), DMAE produced a long-lasting decrease in the rate constant of decay (α) and an increase in the peak current amplitude (Ip). At higher concentrations (10–100 μM), DMAE produced biphasic changes characterized by a transient, marked decrease of α and increase of Ip followed by a long-lasting marked increase of α and decrease of Ip. When DMAE was removed from the bath recovery from block was asymmetrical in that α recovered more quickly than did Ip. Pretreatment with neostigmine or collagenase partially antagonized the initial effects without affecting the steady state effects of DMAE, indicating that the initial effects of DMAE may be, at least in part, due to inhibition of the enzyme acetylcholinesterase. The drug reverses the normal voltage dependence of α without altering the single exponential nature of decay of the EPC. The inward EPC was more markedly blocked than outward EPC, resulting in a highly non-linear current-voltage relation with Ip decreasing with increasing hyperpolarization. This effect may indicate that DMAE causes a voltage-dependent block of closed acetylcholine-activated ion channels.

Key words

Neuromuscular junction Voltage clamp Neostigmine Prejunctional effect Anticholinesterase effect Endplate current 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adams PR (1977) Voltage jump analysis of procaine action at frog endplate. J Physiol (Lond) 268:291–318Google Scholar
  2. Adler M, Olivera AC, Albuquerque EX, Mansour NA, Eldefrawi AT (1979) Reaction of tetraethylammonium with the open and closed conformations of the acetylcholine receptor ionic channel complex. J Gen Physiol 74:129–152Google Scholar
  3. Albuquerque EX, Eldefrawi AT, Eldefrawi ME, Mansour NA, Tsai M-C (1978) Amantidine: Neuromuscular blockade by suppression of ionic conductance of the acetylcholine receptor. Science 199:788–790Google Scholar
  4. Albuquerque EC, Tsai M-C, Aronstam RS, Witkop B, Eldefrawi AT, Eldefrawi ME (1980) Phencyclidine interactions with the ionic channel of the acetylcholine receptor and electrogenic membrane. Proc Natl Acad Sci USA 77:1224–1228Google Scholar
  5. Alkadhi KA, Volle RL (1977) Transmitter mobilization at the frog neuromuscular junction. Arch Intl Pharmacodyn Ther 229:261–275Google Scholar
  6. Alkadhi KA, Reynolds LS, Henderson EG, Volle RL (1981) Multiple actions of DMAE on acetylcholine-activated ionic channels in the frog neuromuscular junction. Soc Neurosci 7:724Google Scholar
  7. Anderson CR, Stevens CF (1973) Voltage clamp analysis of acetylcholine produced endplate current fluctuation at frog neuromuscular junctions. J Physiol (Lond) 235:655–691Google Scholar
  8. Beam KG (1976) A voltage clamp study of the effect of two lidocaine derivatives on the time course of endplate currents. J Physiol (Lond) 258: 279–300Google Scholar
  9. Betz W, Sakmann B (1971) “Disjunction” of frog neuromuscular synapses by treatment with proteolytic enzymes. Nature 232: 94–95Google Scholar
  10. Branisteanu DD, Miyamoto MD, Volle RL (1975) Quantal release parameters during fade of endplate potentials. Naunyn-Schmiedeberg's Arch Pharmacol 288:323–327Google Scholar
  11. Chiou CY, Long JP (1969) Effects of α, α-bis-(dimethylammonium acetaldehyde diethylacetal)-p, p-diacetylbiphenyl bromide (DMAE) on neuromuscular transmission. J Pharmacol Exp Ther 167:344–350Google Scholar
  12. Deguchi T, Narahashi T (1971) Effects of procaine on ionic conductance of endplate membrane. J Pharmacol Exp Ther 176:423–433Google Scholar
  13. Eldefrawi ME, Eldefrawi AT, Aronstam RS, Maleque MA, Warnick JE, Albuquerque EX (1980) [3H] phencyclidine: A probe for the ionic channel of the nicotinic receptor. Proc Natl Acad Sci USA 77:7458–7462Google Scholar
  14. Farley JM, Yeh, JZ, Watanabe S, Narahashi T (1981) Endplate channel block by guanidine derivatives. J Gen Physiol 77:273–293Google Scholar
  15. Gage P, McBurney RN (1975) Effects of membrane potential, temperature and neostigmine on the conductance change caused by a quantum of acetylcholine at the toad neuromuscular junction. J Physiol (Lond) 224:385–407Google Scholar
  16. Goldner MM, Narahashi (1974) Effects of edrophonium on endplate currents in frog skeletal muscle. Eur J Pharmacol 25:362–371Google Scholar
  17. Hall ZW, Kelly RB (1971) Enzymatic detachment of endplate acetylcholinesterase from muscle. Nature 232:62–63Google Scholar
  18. Kordas M, Brzin M, Majcen Z (1975) A comparison of the effect of cholinesterase inhibitors on endplate current and on cholinesterase activity in frog muscle. Neuropharmacology 14:791–800Google Scholar
  19. Lambert JJ, Durant NN, Reynolds LS, Volle RL, Henderson EG (1981) Characterization of endplate conductance in transected frog muscle: Modification by drugs. J Pharmacol Exp Ther 216: 62–69Google Scholar
  20. Lambert JJ, Durant NN, Henderson EG (1983) Drug-induced modification of ionic conductance at the neuromuscular junction. Ann Rev Pharmacol Toxicol 23:505–539Google Scholar
  21. Long JP, Evans CT, Wong S (1967) A pharmacologic evaluation of hemicholinium analogs. J Pharmacol Exp Ther 155:223–230Google Scholar
  22. Magleby KL, Stevens CF (1972) A quantitative description of endplate currents. J Physiol (Lond) 223:173–197Google Scholar
  23. Magleby KL, Terrar DA (1975) Factors affecting the time course of decay of endplate currents: A possible cooperative action of acetylcholine on receptors at the frog neuromuscular junction. J Physiol (Lond) 244:467–495Google Scholar
  24. Masukawa LM, Albuquerque EX (1978) Voltage-and time-dependent action of histrionicotoxin on the endplate current of the frog muscle. J Gen Physiol 72:351–367Google Scholar
  25. Miyamoto MD, Volle RL (1974) Enhancement by carbachol of transmitter release from motor nerve terminals. Proc Natl Acad Sci USA 71:1489–1492Google Scholar
  26. Spivak CE, Maleque MA, Oliveira AC, Masukawa LM, Tokuyama T, Daly JW, Albuquerque EX (1982) Actions of the histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and at the voltage sensitive ion channels of muscle membrane. Mol Pharmacol 21:351–361Google Scholar
  27. Spivak CE, Albuquerque EC (1982) Dynamic properties of the nicotinic acetylcholine receptor ionic channel complex: Activation and blockade. In: Hanin I, Goldberg AM (eds) Progress in cholinergic biology: Model cholinergic synapses. Raven Press, New York, pp 323–357Google Scholar
  28. Volle LR (1973) Frequency dependent decrease of quantal content in a drug-treated neuromuscular junction. Naunyn-Schmiedeberg's Arch Pharmacol 278:271–284Google Scholar
  29. Volle RL, Henderson EG (1975) Pre- and postjunctional neuromuscular blockade by carbachol. Naunyn-Schmiedeberg's Arch Pharmacol 291:359–370Google Scholar
  30. Volle RL, Alkadhi KA, Branisteanu DD, Reynolds LS, Epstein PM, Smilowitz H, Lambert JJ, Henderson EG (1982) Ketamine and ditran block endplate ion conductance and [3H] phencyclidine binding to electric organ membrane. J Pharmacol Exp Ther 221:570–576Google Scholar
  31. Wong S, Long JP (1968) Antagonism of ganglionic stimulants by α,α-bis-(dimethylammonium acetaldehyde diethylacetal)-p, p-diacetylbipheny] bromide (DMAE). J Pharmacol Exp Ther 164:176–184Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • Karim A. Alkadhi
    • 1
  1. 1.Department of PharmacologyUniversity of HoustonHoustonUSA

Personalised recommendations