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Effectiveness of theophylline to increase cyclic AMP levels and force of contraction in electrically paced guinea-pig auricles. Comparison with isoprenaline, calcium and ouabain

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Summary

The effects of theophylline (3×10−5 M–5×10−3 M), isoprenaline (10−6 M), excess calcium (7.2 mM) and ouabain (3×10−7 M) on force of contraction and c-AMP content were studied in electrically driven (frequency 3 Hz) left auricles isolated from guinea pigs pretreated with reserpine.

  1. 1.

    Theophylline (2×10−3 M) increased c-AMP consistently. The theophylline-induced increase in c-AMP proceeded very rapidly. It became significant after an incubation period of 5 s, reached its peak after 5 min and then remained stable. The positive inotropic effect of theophylline also developed very rapidly, reached its peak after 1 min and then declined. The increase in force of contraction corresponded to the increase in c-AMP, but the decline of the positive inotropic effect occurred while c-AMP remained elevated.

  2. 2.

    The concentration-response curves for the theophylline-induced increases in c-AMP and force of contraction were virtually parallel at concentrations up to 2×10−3 M.

  3. 3.

    Washout of the effects of theophylline on c-AMP and force of contraction was also similar. Complete reversal occurred within 15 min.

  4. 4.

    The effects of theophylline on c-AMP and force of contraction were not affected by 10−7 M propranolol added 30 min before theophylline.

  5. 5.

    Isoprenaline (10−6 M) increased c-AMP and force of contraction to approximately the same extent upon incubation for up to 30 min.

  6. 6.

    Ouabain (3×10−7 M) or the elevation of the extracellular calcium concentration to 7.2 mM increased the force of contraction without producing a detectable increase in c-AMP.

  7. 7.

    It is concluded that the theophylline-produced increase in force of contraction may be the result of an increase in c-AMP and a subsequent increase in slow inward current. This effect may be counteracted by a direct, c-AMP independent effect of theophylline on intracellular calcium stores which could account for the decline of the positive inotropic effect of theophylline during prolonged exposure and at high concentrations.

  8. 8.

    The present data also support the view that the positive inotropic effect of isoprenaline is mediated by c-AMP, whereas the effects of ouabain and excess calcium on force of contraction appear to be independent of the c-AMP system.

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  1. Pharmakologisches Institut der Universität Mainz, Obere Zahlbacher Strasse 67, D-6500, Mainz, Germany

    Claudia Dönges, Martin Heitmann, Harald Jungbluth, Thomas Meinertz & Barbara Schmelzle

  2. Institut für Pharmakologie und Toxikologie, Abteilung III (Biochemische Pharmakologie), Medizinische Hochschule Hannover, Karl-Wiechert-Allee 9, D-3000, Hannover 61, Germany

    Hasso Scholz

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  1. Claudia Dönges
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  2. Martin Heitmann
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Dönges, C., Heitmann, M., Jungbluth, H. et al. Effectiveness of theophylline to increase cyclic AMP levels and force of contraction in electrically paced guinea-pig auricles. Comparison with isoprenaline, calcium and ouabain. Naunyn-Schmiedeberg's Arch. Pharmacol. 301, 87–97 (1977). https://doi.org/10.1007/BF00501422

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