Phosphodiesterase inhibition and positive inotropy in failing human myocardium

  • W. Schmitz
  • T. Eschenhagen
  • U. Mende
  • F. U. Müller
  • J. Neumann
  • H. Scholz


Positive inotropic effects of phosphodiesterase inhibitors like 3-isobutyl-l-methylxanthine (IBMX), pimobendan, adibendan, milrinone, saterinone, and enoximone are greatly diminished in isolated heart muscle preparations from human failing myocardium as compared to nonfailing myocardium. This is accompanied by a reduced increase in cAMP content in intact isometrically contracting human trabeculae. With anion exchange chromatography four peaks of phosphodiesterase activities (PDE I–IV) could be separated from both nonfailing and failing human myocardium. Substrate specificity, Km, and Vmax were similar in nonfailing and failing myocardium. Furthermore, the PDE inhibitors investigated exhibited similar IC50-values in both tissues, indicating that the sensitivity of the enzymes from nonfailing and failing tissue was unchanged. Thus, changes in PDE are probably not responsible for the reduced positive inotropic and cAMP-increasing effects of PDE inhibitors in human failing heart muscle preparations. Instead, an increase in signal transducing inhibitory G-proteins may keep the adenylyl cyclase at reduced activity, resulting in an attenuated formation of cAMP, even in the presence of PDE inhibitors.

Key words

Phosphodiesterase inhibitors heart failure human myocardium cAMP 


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  1. 1.
    Bauer AC, Schwabe U (1980) An improved assay of cyclic 3’,5’-nucleotide phosphodiesterases with QAE-sephadex columns. Naunyn-Schmiedeberg’s Arch Pharmacol 311: 193–198PubMedCrossRefGoogle Scholar
  2. 2.
    Bethke T, Klimkiewicz A, Kohl C, von der Leyen H, Mehl H, Mende U, Meyer W, Neumann J, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalmar P, and Haverich A (1991) Effects of Isomazole on Force of Contraction and Phosphodiesterase Isoenzymes I–IV in Nonfailing and Failing Human Hearts Journal of Cardiovascular Pharmacology 18:386–397 1991 Raven Press, Ltd., New YorkGoogle Scholar
  3. 3.
    Böhm M, Beuckelmann D, Brown L, Feiler G, Lorenz B, Näbauer M, Kemkes B, Erdmann E (1988) Reduction of β-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium. Eur Heart J 9: 844–852PubMedGoogle Scholar
  4. 4.
    Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med 307: 205–211PubMedCrossRefGoogle Scholar
  5. 5.
    Bristow MR, Port JD, Sandoval AB, Rasmussen R, Ginsburg R, Feldman AM (1989) β-Adrenergic receptor pathways in the failing human heart. Heart Failure 5: 77–90Google Scholar
  6. 6.
    Erdmann E (1988) The effectiveness of inotropic agents in isolated cardiac preparations from the human heart. Klin Wochenschr 66: 1–6PubMedCrossRefGoogle Scholar
  7. 7.
    Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Dop C van (1988) Increase of the 40,000-mol wt pertussis toxin substrate ( G protein) in the failing human heart. J Clin Invest 82: 189–197Google Scholar
  8. 8.
    Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossmann W, Morgan JP (1987) Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75: 331–339PubMedCrossRefGoogle Scholar
  9. 9.
    Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN (1982) Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 49: 1659–1666PubMedCrossRefGoogle Scholar
  10. 10.
    von der Leyen H, Mende U, Meyer W, Neumann J, Nose M, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalmar P, Haveric A (1991) 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: 90–100PubMedGoogle Scholar
  11. 11.
    Neumann J, Schmitz W, Scholz H, Meyerinck L von, Döring V, Kalmár P (1988) Increase in myocardial Grproteins in heart failure. Lancet II: 936–937Google Scholar
  12. 12.
    Reeves ML, Leigh BK, England PJ (1987) The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Biochem J 241: 535–541PubMedGoogle Scholar
  13. 13.
    Schmitz W, Scholz H, Erdmann E (1987) Effects of α- and β-adrenergic agonists, phosphodiesterase inhibitors and adenosine on isolated human heart muscle preparations. Trends Pharmacol Sci 8: 447–450CrossRefGoogle Scholar
  14. 14.
    Steinfath M, Danielsen W, von der Leyen H, Mende U, Meyer W, Neumann J, Nose M, Reich T, Schmitz W, Scholz H, Starbatty J, Stein B, Döring V, Kalmar P, Haverich A (1992) Reduced α1 and β2-adrenoceptor mediated positive inotropic effects in human end-stage heart failure. Brit J Pharmacol (in press)Google Scholar
  15. 15.
    Thomas JA, Marks BH (1978) Plasma norepinephrine in congestive heart failure. Am J Cardiol 41: 233–243PubMedCrossRefGoogle Scholar
  16. 16.
    Thompson WJ, Appleman MM (1971) Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry 10: 311–316PubMedCrossRefGoogle Scholar
  17. 17.
    Thompson WJ, Terasaki WL, Epstein PM, Strada SJ (1979) Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv Cyclic Nucleotide Res 10: 69–92PubMedGoogle Scholar
  18. 18.
    Wilmshurst PT, Walker JM, Fry CH, Mounsey JP, Twort CHC, Williams BT, Davies MJ, Webb-Peploe MM (1984) Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovasc Res 18: 302–309PubMedCrossRefGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co.KG, Darmstadt 1992

Authors and Affiliations

  • W. Schmitz
    • 1
    • 2
  • T. Eschenhagen
    • 1
  • U. Mende
    • 1
  • F. U. Müller
    • 1
  • J. Neumann
    • 1
  • H. Scholz
    • 1
  1. 1.Abteilung Allgemeine PharmakologieUniversitäts-Krankenhaus Eppendorf, Universität HamburgGermany
  2. 2.Abteilung Allgemeine PharmakologieUniversitäts-Krankenhaus EppendorfGermany

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