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Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations

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Summary

The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the aβ-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydroouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors.

To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I–III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I–III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored.

These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure. Furthermore, the concomitant application of a β-adrenoceptor agonist and a phosphodiesterase inhibitor might be beneficial in terminal heart failure refractory to conventional therapeutic regimens.

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Authors and Affiliations

  1. Abteilung Allgemeine Pharmakologie, Federal Republic of Germany

    Heiko von der Leyen, Ulrike Mende, Wilfried Meyer, Joachim Neumann, Monika Nose, Wilhelm Schmitz, Hasso Scholz, Jutta Starbatty, Birgitt Stein & Holger Wenzlaff

  2. Abteilung für Herz- and Gefäβchirurgie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Martinistrasse 52, W-2000, Hamburg 20, Federal Republic of Germany

    Volker Döring & Peter Kalmir

  3. Klinik für Thorax-, Herz- and Gefäβchirurgie, Medizinische Hochschule Hannover, Konstanty-Gutschow-Strasse 8, W-3000, Hannover 61, Federal Republic of Germany

    Axel Haverich

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  1. Heiko von der Leyen
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  2. Ulrike Mende
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  3. Wilfried Meyer
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Additional information

Some of the results reported in this paper have already been presented in abstract form at the 61 st Session of the American Heart Association, Washington, DC, Nov. 1988 (von der Leyen et al., Circulation 78 (Suppl II): 11-360, 1988), at the Fall Meeting of the German Society of Pharmacology and Toxicology, Sept. 1988 (Schmitz et al., Naunyn-Schmiedeberg's Arch Pharmacol 338 (Suppl): R 16, 1988), at the 30th Spring Meeting of the German Society of Pharmacology and Toxicology, March 1989 (Meyer et al., Naunyn-Schmiedeberg's Arch Pharmacol 339 (Suppl): R 53, 1989), and at the XIII Congress of the International Society For Heart Research, Ann Arbor, MI, May 1989 (Meyer et al., J Mol Cell Cardiol 21 (Suppl 11): S. 50, 1989) mis|Send offprint requests to Wilfried Meyer at the above address

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von der Leyen, H., Mende, U., Meyer, W. et al. Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. Naunyn-Schmiedeberg's Arch Pharmacol 344, 90–100 (1991). https://doi.org/10.1007/BF00167387

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