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Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium

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Summary

The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.C1 and milrinone at A1 adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A1 adenosine receptors, all compounds inhibited 3H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the Ki-values, the rank order of potency was saterinone > sulmazole > UD-CG 212.C1 > milrinone. The new inotropic agents also displaced the binding of 3H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean Ki-values were considerably higher at m-cholinoceptors than at A1 adenosine receptors. The rank order of potency was saterinone > sulmazole > UD-CG 212.Cl > milrinone. Competition of the A1 adenosine receptor agonist R-PIA to 3H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient nH = 0.63) and revealed two affinity states of the A1 adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient nH = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the superhigh affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p. Accordingly, in isolated, electrically driven human atrial trabeculae, the negative inotropic effect of adenosine was antagonized concentration-dependently by saterinone, sulmazole and UD-CG 212.Cl. Similarly the negative inotropic effect of carbachol was antagonized concentration-dependently by saterinone. It is concluded that the new inotropic agents bind to A1 adenosine receptors and that their interaction is of antagonist nature. This mechanism might contribute to their capacity to enhance force of contraction by stimulation of cAMP-formation in addition to phosphodiesterase inhibition. The effects of saterinone may be partially due to antagonism at m-cholinoceptors. This is presumably not the case with the other inotropic agents studied given their low affinity for this receptor.

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Authors and Affiliations

  1. Medizinische Klinik I der Universität München, Klinikum Großhadern, Marchioninistrasse 15, D-8000, München 70, Federal Republic of Germany

    Martin Ungerer, Michael Böhm, Robert H. G. Schwinger & Erland Erdmann

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  1. Martin Ungerer
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  2. Michael Böhm
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  3. Robert H. G. Schwinger
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  4. Erland Erdmann
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Supported by the Deutsche Forschungsgemeinschaft

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Ungerer, M., Böhm, M., Schwinger, R.H.G. et al. Antagonism of novel inotropic agents at A1 adenosine receptors and m-cholinoceptors in human myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 341, 577–585 (1990). https://doi.org/10.1007/BF00171739

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  • DOI: https://doi.org/10.1007/BF00171739

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