Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE^sub 1^ in mice

Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial [beta]^sub 1^- and [beta]^sub 2^-adrenoceptors despite the high content of sinoatrial cAMP. The function of...

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Published in:Naunyn-Schmiedeberg's archives of pharmacology 2016-02, Vol.389 (2), p.177
Main Authors: Galindo-tovar, Alejandro, Vargas, María Luisa, Kaumann, Alberto J
Format: Article
Language:English
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Summary:Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial [beta]^sub 1^- and [beta]^sub 2^-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE^sub 1^ elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE^sub 1^ (1 [mu]M). Bay 60-7550 (1 [mu]M), but not EHNA (10 [mu]M), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 [mu]M), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 [mu]M) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE^sub 1^ was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE^sub 1^, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-015-1178-2