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Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium

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Abstract

Acting through a low-affinity site of the β1-adrenoceptor (β1LAR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 µM) on the (−)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 ± 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (−)-CGP12177 (−logEC50M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 ± 9% of the effect of 200 µM (−)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (−)-CGP12177 (−logEC50M = 7.4) but concurrent rolipram + cilostamide caused potentiation (−logEC50M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the β1LAR-induced cAMP compartment through which (−)-CGP12177 causes tachycardia. In contrast to the (−)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (−)-CGP12177-evoked increases of left atrial contractility through β1LAR.

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Acknowledgements

This work was supported by grant PI052338 Fondo Investigación Sanitaria of the Ministerio de Sanidad y Consumo, and the Séneca Foundation, of Spain.

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Authors and Affiliations

  1. Department of Pharmacology, University of Murcia and Research Unit of the University Hospital Virgen de la Arrixaca, Murcia, Spain

    Alejandro Galindo-Tovar & Maria Luisa Vargas

  2. Department of Physiology, Development and Neuroscience, Cambridge University, Downing Street, Physiology Building, Cambridge, CB2 3EG, UK

    Alberto J. Kaumann

Authors
  1. Alejandro Galindo-Tovar
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  2. Maria Luisa Vargas
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  3. Alberto J. Kaumann
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Correspondence to Alberto J. Kaumann.

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Galindo-Tovar, A., Vargas, M.L. & Kaumann, A.J. Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium. Naunyn-Schmied Arch Pharmacol 379, 379–384 (2009). https://doi.org/10.1007/s00210-008-0367-7

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  • DOI: https://doi.org/10.1007/s00210-008-0367-7

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