Summary
Experiments were carried out in isolated perfused rat hearts.
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1.
The presence of tropolone (100 \gmol/l), an inhibitor of catechol-O-methyl transferase (COMT), significantly potentiated the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/1).
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2.
Two uptake2 inhibitors, 3-O-methylisoprenaline (100 gmol/1) and normetanephrine (100 \gmmol/l), induced a positive chronotropic response, but corticosterone (100 \gmmol/l) and hydrocortisone (100 gmol/1) had no such effect.
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3.
3-O-methylisoprenaline (100 \gmmol/l) and normetanephrine (100 \gmmol/l) enhanced the positive chronotropic response to isoprenaline (0.1, 1, 3 and 10 nmol/1). Corticosterone (100 \gmmol/l) potentiated the positive chronotropic response to isoprenaline (0.1 and 1 nmol/1). Hydrocortisone (30 \gmmol/l) enhanced the response to 0.1 nmol/l isoprenaline but did not affect the positive chronotropic responses to 1, 3 or 10 nmol/l isoprenaline.
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4.
The addition of uptake2 inhibitors (3-O-methylisoprenaline, 100 gmol/1; normetanephrine, 100 \gmmol/l; corticosterone, 100 \gmmol/l) to the perfusion medium significantly reduced the positive chronotropic response to the perfusion with isoprenaline (3 nmol/l) and tropolone (100 \gmmol/l).
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5.
The accumulation of 3H-isoprenaline in the heart perfused with 3H-isoprenaline (1, 10 and 100 nmol/1) was significantly increased by the presence of tropolone (100 \gmmol/l): the accumulation for 1, 10 and 100 nmol/1 of 3H-isoprenaline was 5.07, 47.0 and 500 pmol/g, respectively.
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6.
The high accumulation observed during perfusion with 3H-isoprenaline (3 nmol/1) and tropolone (100 gmol/1) was significantly decreased by the addition of an uptake2 inhibitor, 3-O-methylisoprenaline (100 gmol/1), normetanephrine (100 gmol/1) or corticosterone (100 \gmmol/l), but not by hydrocortisone (30 \gmmol/l).
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7.
From these results, it is suggested that the inhibitory effects of uptake2 inhibitors on the positive chronotropic response to isoprenaline in the presence of a COMT inhibitor might be related to the decrease in accumulation of isoprenaline in the perfused rat hearts, and that the extraneuronally accumulated isoprenaline in the rat heart might activate intracellular \gb-adrenoceptors.
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This study was supported by a Grant-in-Aid for Scientific Research (61570101) from the Ministry of Education, Science and Culture, Japan
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Magaribuchi, T., Hama, T., Kurahashi, K. et al. Effects of extraneuronal uptake inhibitors on the positive chronotropic response to isoprenaline and on the accumulation of isoprenaline in perfused rat heart after inhibition of catechol-O-methyl transferase. Naunyn-Schmiedeberg's Arch Pharmacol 335, 123–128 (1987). https://doi.org/10.1007/BF00177712
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DOI: https://doi.org/10.1007/BF00177712