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Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

  • Cardiovascular System
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Abstract

Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the β-adrenoreceptor (β-AR)–cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained β-AR activation produced by administration of isoproterenol (ISO) (50 μg kg−1 day−1 i.p. for 1 month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure–volume and stress–strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca2+ in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic β-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained β-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca2+-induced Ca2+ release.

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Acknowledgements

Dr. Oleg E. Osadchii is a recipient of a postdoctoral fellowship from the Research Committee of the University of the Witwatersrand. We are grateful to the University Research Committee and the Iris Ellen Hodges and H.E. Griffin Charitable Trusts that funded these studies.

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  1. Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown 2193, Johannesburg, South Africa

    Oleg E. Osadchii, Angela J. Woodiwiss & Gavin R. Norton

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  1. Oleg E. Osadchii
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  2. Angela J. Woodiwiss
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  3. Gavin R. Norton
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Correspondence to Oleg E. Osadchii.

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Osadchii, O.E., Woodiwiss, A.J. & Norton, G.R. Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation. Pflugers Arch - Eur J Physiol 452, 155–163 (2006). https://doi.org/10.1007/s00424-005-0025-6

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