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Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart

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Summary

Chronic β-adrenoceptor stimulation leads to desensitization of the myocardial adenylyl cyclase signalling pathway which includes β-adrenoceptor downregulation and upregulation of Gi-protein α-subunits. However, these investigations have mainly been done in cellular preparations. In this study we report that isoprenaline infusion in vivo leads to an increase in myocardial Gia and present evidence for functional consequences of this increase.

Rats were treated by a 4-day subcutaneous infusion with isoprenaline (2.4 mg/kg·d), propranolol (9.9 mg/kg·d) and triiodothyronine (T3, 0.5 mg/kg·d) for comparison. Isoprenaline treatment increased the pertussis toxin-sensitive amount of Gia by 22±6% and decreased β1- and β2-adrenoceptor density from 35±4 to 23±6 fmol/mg protein and 24±4 to 8±6 fmol/mg protein, respectively. Contraction experiments on electrically driven papillary muscles revealed that the negative inotropic potency of the M-cholinoceptor agonist carbachol in the presence of isoprenaline was increased as compared to control (mean EC50-values: 0.04 μmol/l vs. 0.28 μmol/l). All isoprenaline-induced effects were antagonized by simultaneously administered propranolol. T3 treatment had no influence on the parameters investigated.

The results suggest that chronic β-adrenoceptor stimulation desensitizes myocardial adenylyl cyclase by at least two mechanisms: β-adrenoceptor downregulation leading to diminished signal transduction in the stimulatory pathway and Giα upregulation leading to sensitization of the inhibitory pathway. Such adaptation might protect the heart from chronic exposure to catecholamines in heart diseases with elevated plasma catecholamine levels.

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Authors and Affiliations

  1. Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany

    Ulrike Mende, Thomas Eschenhagen, Birgit Geertz, Wilhelm Schmitz, Hasso Scholz, Jan Schulte am Esch, Rainer Sempell & Markus Steinfath

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  1. Ulrike Mende
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  2. Thomas Eschenhagen
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  3. Birgit Geertz
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  4. Wilhelm Schmitz
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  5. Hasso Scholz
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  6. Jan Schulte am Esch
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  7. Rainer Sempell
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  8. Markus Steinfath
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Send offprint requests to U. Mende at the above address

Parts of the results have been presented at the Wintertagung of the Deutsche Gesellschaft für Pharmakologie und Toxikologie in Hannover, 1990 (Mende et al., Naunyn-Schmiedebergs Arch Pharmacol 342 [Suppl]:R24). The work has been supported by the Deutsche Forschungsgemeinschaft

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Mende, U., Eschenhagen, T., Geertz, B. et al. Isoprenaline-induced increase in the 40/41 kDa pertussis toxin substrates and functional consequences on contractile response in rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 345, 44–50 (1992). https://doi.org/10.1007/BF00175468

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  • DOI: https://doi.org/10.1007/BF00175468

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