Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.

E. M. Silinsky*, S. M. Vogel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

1. A series of related methylxanthines were studied for their effects on the kinetics of decay of end‐plate currents (e.p.c.s) and miniature end‐plate currents (m.e.p.c.s) at motor end‐plates of the frog. 2. Isobutyl methylxanthine (IBMX, 50 microM‐3 mM) produced a concentration‐dependent depression of the peak e.p.c. and m.e.p.c. amplitude and a change in the kinetics of e.p.c. and m.e.p.c. decay from the normal single‐exponential to a double‐exponential function. Drug effects of this nature are generally attributed to open‐channel blockade. 3. After wash‐out of IBMX, the decay of the e.p.c. or m.e.p.c. was restored to a single‐exponential function but with a significantly prolonged time constant. 4. Caffeine or theophylline derivatives (0.1‐4 mM), during exposure to drug, produced effects similar to those observed after the application of IBMX; namely a prolongation of the time course of e.p.c.s and m.e.p.c.s without changing the single‐exponential nature of the function. 5. Computer simulations were made of the m.e.p.c.s in IBMX. The effects of IBMX could be fitted to the sequential model of channel block only if the prolonged time constant observed upon wash‐out was used for the rate constant of channel closure. Independent calculations of the rate constant of channel closure during IBMX application were in agreement with those measured during wash‐out. 6. The theophylline derivative 8‐phenyltheophylline, a selective adenosine receptor blocker with minimal effects on phosphodiesterase (PDE), increased the time constant of e.p.c. decay in a manner similar to theophylline and caffeine. Non‐xanthine PDE inhibitors, either had no effect on m.e.p.c. decay (papaverine) or decreased the time constant of decay (RO 20‐1724). It is thus unlikely that PDE inhibition is responsible for the post‐junctional effects of IBMX. 7. IBMX (50 microM‐2 mM) increased quantal ACh release in the virtual absence of extracellular calcium and also increased the efficacy of adenosine derivatives in inhibiting ACh release. Adenosine (10‐100 microM) or 2‐chloroadenosine (1‐10 microM) had no effect on the time constant of e.p.c. decay nor did these adenosine receptor agonists alter the post‐junctional actions of IBMX. The effects of IBMX on end‐plate channel kinetics are thus not due to the blockade of adenosine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Original languageEnglish (US)
Pages (from-to)33-44
Number of pages12
JournalThe Journal of Physiology
Volume390
Issue number1
DOIs
StatePublished - Sep 1 1987

ASJC Scopus subject areas

  • Physiology

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