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Phosphodiesterases do not limit β1-adrenoceptor-mediated sinoatrial tachycardia: evidence with PDE3 and PDE4 in rabbits and PDE1–5 in rats

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Abstract

The mammalian heart expresses at least five phosphodiesterases (PDE1–5). Catecholamines produce surges of inotropically relevant cAMP through β1-adrenoceptor stimulation. cAMP is mainly hydrolysed by PDE3 and/or PDE4 thereby blunting contractility. Basal sinoatrial beating rate in mouse, rat, piglet and rabbit sinoatrial cells is reduced by PDE3 and/or PDE4 through hydrolysis of cAMP. However, in rodents, the tachycardia elicited by catecholamines through production of cAMP by β-adrenoceptor activation is not controlled by PDE3 and PDE4, despite a blunting effect of PDE3 or/and PDE4 on basal sinoatrial beating, but it is unknown whether PDE3 limits catecholamine-evoked tachycardia in the rabbit. Since rabbit sinoatrial cells are an important model for pacemaker research, we investigated whether the positive chronotropic effects of (−)-noradrenaline on spontaneously beating right atria of the rabbit are potentiated by inhibition of PDE3 with cilostamide (300 nM). We also studied the sinoatrial effects of the PDE4 inhibitor rolipram (10 μM) and its influence on the responses to (−)-noradrenaline. For comparison, we investigated the influence of cilostamide and rolipram on the positive inotropic responses to (−)-noradrenaline on rabbit left atria and right ventricular papillary muscles. Cilostamide and concurrent cilostamide + rolipram, but not rolipram alone, increased sinoatrial rate by 15% and 31% of the effect of (−)-isoprenaline (200 µM) but the PDE inhibitors did not significantly change the chronotropic potency of (−)-noradrenaline. In contrast in papillary muscle, the positive inotropic effects of (−)-noradrenaline were potentiated 2.4-, 2.6- and 44-fold by cilostamide, rolipram and concurrent cilostamide + rolipram, respectively. In left atrium, the positive inotropic effects of (−)-noradrenaline were marginally potentiated by cilostamide, as well as potentiated 2.7- and 32-fold by rolipram and by concurrent cilostamide and rolipram respectively. To compare the influence of PDE1–5 on basal sinoatrial rate and (−)-noradrenaline-evoked tachycardia, we investigated on rat right atria the effects of selective inhibitors. The PDE4 inhibitor rolipram and non-selective inhibitor isobutyl-methylxanthine caused tachycardia with –logEC50s of 7.2 and 5.0 and E max of 18% and 102% of (−)-isoprenaline, respectively. Rolipram did not change the chronotropic potency of (−)-noradrenaline. At high concentrations (10–30 µM), the PDE1, PDE3 and PDE5 inhibitors 8-methoxymethyl-3-isobutyl-1-methylxanthine, cilostamide and sildenafil, respectively, caused marginal tachycardia but did not significantly change the chronotropic potency of (−)-noradrenaline. The PDE2-selective inhibitor erythro-9-[2-hydroxy-3-nonyl]adenine caused marginal bradycardia at 30 µM and tended to reduce the chronotropic potency of (−)-noradrenaline. Rabbit PDE3 reduces basal sinoatrial rate. Although PDE4 only marginally reduces rate, under conditions of PDE3 inhibition, it further reduces sinoatrial rate. Both PDE3 and PDE4 control atrial and ventricular positive inotropic effects of (−)-noradrenaline. In contrast, neither PDE3 nor PDE4 limit the sinoatrial tachycardia induced by (−)-noradrenaline. In the rat, only PDE4, but not PDE1, PDE2, PDE3 and PDE5, reduces basal sinoatrial rate. None of the five rat PDEs limits the (−)-noradrenaline-evoked tachycardia. Taken together, these results confirm and expand evidence for our proposal that the cAMP-compartment modulating basal sinoatrial rate, controlled by PDE3 and/or PDE4, is different from the PDE-resistant cAMP compartment involved in β1-adrenoceptor-mediated sinoatrial tachycardia.

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Acknowledgement

This work was supported by the Séneca Foundation.

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Authors and Affiliations

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

    Alberto J. Kaumann

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

    Alejandro Galindo-Tovar, Elisa Escudero & María Luisa Vargas

  3. Veterinary School, University of Murcia, Murcia, Spain

    Elisa Escudero

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  1. Alberto J. Kaumann
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  2. Alejandro Galindo-Tovar
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  3. Elisa Escudero
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  4. María Luisa Vargas
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Correspondence to Alberto J. Kaumann.

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Kaumann, A.J., Galindo-Tovar, A., Escudero, E. et al. Phosphodiesterases do not limit β1-adrenoceptor-mediated sinoatrial tachycardia: evidence with PDE3 and PDE4 in rabbits and PDE1–5 in rats. Naunyn-Schmied Arch Pharmacol 380, 421–430 (2009). https://doi.org/10.1007/s00210-009-0445-5

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