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Extraneuronal removal, accumulation and O-methylation of isoprenaline in the perfused heart

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Summary

  1. 1.

    Isolated rat and guinea-pig hearts were perfused with 0.95 μM (±)-isoprenaline or 3H(±)-isoprenaline, a catecholamine which is taken up by extraneuronal mechanisms only. From measurements of the arterio-nevous difference (by fluorimetry and by scintillation counting, respectively) the rate of removal of the amine from the perfusion fluid was measured; in addition, the rate of appearance of its metabolite (3-O-methyl-3H-isoprenaline; 3H-OMI) was determined in the venous effluent as well as the accumulation of 3H-isoprenaline and 3H-OMI in the heart.

  2. 2.

    Experiments with sodium thiocyanate and 14C-sorbitol showed that these agents distributed into the extracellular space (about 350 μl/g; t/2 for efflux of about 1.2 min) and into ventricular and atrial cavities (about 1500 μl/g; t/2 for efflux of 0.1 to 0.2 min).

  3. 3.

    The removal of 3H-isoprenaline from the perfusion fluid declined biphasically with time; after an initial rapid decline the rate of removal approached steadystate levels within about 30 min. After block of COMT (by the presence of 100 μM U-0521) the second phase of decline approached zero. In the absence of U-0521 the steady-state rate of removal was 10 times higher in rat than in guinea-pig hearts; in the presence of U-0521 the approach to zero was faster for guinea-pig than for rat hearts.

  4. 4.

    When COMT was intact, 3H-OMI appeared in the venous effluent, first at a rapidly increasing rate, from the 9th minute of perfusion onward at a steady rate which was identical with the steady-state rate of removal of 3H-isoprenaline. No 3H-OMI was detected after block of COMT.

  5. 5.

    The accumulation of 3H-isoprenaline in the heart reached a steady level within about 30 min; block of COMT increased the time required for approach to steady levels and increased the accumulation of 3H-isoprenaline in the rat (but not in the guinea-pig) heart. When COMT was intact, the accumulation of 3H-OMI in the heart reached steady-state levels within 10 min.

  6. 6.

    The time-dependent decline of the rate of removal of 3H-isoprenaline by hearts whose COMT had been inhibited was due to a time-dependent increase of the rate of efflux of the amine from the stores; there did not seem to be any change in the rate of gross influx.

  7. 7.

    Isoprenaline-induced ventricular fibrillation reduced the rate of O-methylation of 3H-isoprenaline significantly.

  8. 8.

    Perfusion of hearts with 0.095 μM (±)-isoprenaline resulted in a significantly greater accumulation of the amine in rat than in guinea-pig and rabbit hearts.

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Würzburg, Germany

    H. Bönisch & U. Trendelenburg

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  1. H. Bönisch
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  2. U. Trendelenburg
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Additional information

Some of the findings of this study were communicated to the German Pharmacological Society (Bönisch and Uhlig, 1973).

Supported by the Deutsche Forschungsgemeinschaft.

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Bönisch, H., Trendelenburg, U. Extraneuronal removal, accumulation and O-methylation of isoprenaline in the perfused heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 283, 191–218 (1974). https://doi.org/10.1007/BF00501145

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  • DOI: https://doi.org/10.1007/BF00501145

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