Abstract
Myocardial PDE2 activity increases in terminal human heart failure and after isoprenaline infusion in rat heart. PDE2 inhibitors do not potentiate the murine sinoatrial tachycardia produced by noradrenaline. We investigated whether isoprenaline infusion induces PDE2 to decrease the chronotropic and inotropic effects of catecholamines in rat heart. Sprague-Dawley rats were infused with isoprenaline (2.4 mg kg−1 day−1) for 3 days. We used spontaneously beating right atria, paced right ventricular strips and left ventricular papillary muscles. The effects of the PDE2 inhibitors EHNA (10 μM) and Bay 60-7550 (0.1–1 μM) were investigated on the cardiostimulation produced by noradrenaline (ICI118551 50 nM present to block β2-adrenoceptors) and adrenaline (CGP20712A 300 nM present to block β1-adrenoceptors). Hydrolysis of cAMP by PDE2 was measured by radioenzyme assay. Bay 60-7550 but not EHNA increased sinoatrial beating. A stable tachycardia elicited by noradrenaline (10 nM) or adrenaline (1 μM) was not increased by the PDE2 inhibitors. Isoprenaline infusion increased the hydrolytic PDE2 activity threefold in left ventricle, reduced the chronotropic and inotropic effects and potency of noradrenaline and abolished the effects of adrenaline. The potency of the catecholamines was not increased by the PDE2 inhibitors. Neither EHNA nor Bay 60-7550 potentiated the effects of the catecholamines. Rat PDE2 decreased basal sinoatrial beating but did not reduce the sinoatrial tachycardia or increases of ventricular force mediated through β1- and β2-adrenoceptors. The β-adrenoceptor desensitization induced by the isoprenaline infusion was not reversed by the PDE2 inhibitors despite the increased hydrolysis of cAMP by PDE2.
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Acknowledgments
We thank Juana María Hidalgo Cespedes for technical assistance and Antonio Piñuela for constructing Fig. 10. This work was supported by a grant of the Ministerio de Ciencia e Innovación (SAF/FEDER 2013-47076) and grant Plan Propio de Investigación PMAFI/07/14 of the Universidad Católica San Antonio de Murcia.
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A.G., ML.V. and A.K. performed the research. A.G., ML.V. and A.K. designed the research study. A.G., ML.V. and A.K. analyzed the data. A.K. wrote the paper.
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Galindo-Tovar, A., Vargas, M.L. & Kaumann, A. Phosphodiesterase PDE2 activity, increased by isoprenaline, does not reduce β-adrenoceptor-mediated chronotropic and inotropic effects in rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 391, 571–585 (2018). https://doi.org/10.1007/s00210-018-1480-x
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DOI: https://doi.org/10.1007/s00210-018-1480-x