Ontogenic changes of the control by phosphodiesterase‐3 and ‐4 of 5‐HT responses in porcine heart and relevance to human atrial 5‐HT4 receptors

Background and purpose:  Atrial inotropic responses to 5‐HT mediated through 5‐HT4 receptors fade, presumably through phosphodiesterase (PDE) activity. We investigated the influence of a selective inhibitor of PDE3 (cilostamide) or of PDE4 (rolipram) on the fade of 5‐HT responses in atrial muscle. E...

Full description

Saved in:
Bibliographic Details
Published in:British journal of pharmacology 2009-01, Vol.156 (2), p.237-249
Main Authors: Galindo‐Tovar, Alejandro, Vargas, Maria Luisa, Escudero, Elisa, Kaumann, Alberto J.
Format: Article
Language:English
Subjects:
5‐HT4 receptors
Biological and medical sciences
cAMP
Medical sciences
Pharmacology. Drug treatments
Phosphodiesterases‐3 and ‐4
porcine and human atrium
Research Paper
sinoatrial node
ventricle
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background and purpose:  Atrial inotropic responses to 5‐HT mediated through 5‐HT4 receptors fade, presumably through phosphodiesterase (PDE) activity. We investigated the influence of a selective inhibitor of PDE3 (cilostamide) or of PDE4 (rolipram) on the fade of 5‐HT responses in atrial muscle. Experimental approach:  5‐HT responses were compared, ex vivo, on sinoatrial beating rate of newborn piglets, porcine atrial and ventricular force, and human atrial force. cAMP levels were assessed in piglet atrium. Key results:  5‐HT‐evoked sinoatrial tachycardia did not fade and was not potentiated by cilostamide (300 nmol·L−1) or rolipram (1 µmol·L−1). Inotropic responses to 5‐HT faded in atria from piglets, adolescent pigs and humans. Cilostamide reduced atrial fade of 5‐HT responses in adolescent pigs and humans but not in newborn piglets. Cilostamide disclosed 5‐HT ventricular responses in newborn, but not adolescent pigs. Rolipram reduced fade of atrial 5‐HT responses in newborn and adolescent pigs but not in humans. Concurrent cilostamide + rolipram abolished fade of 5‐HT responses in porcine left atria and facilitated ventricular 5‐HT responses, but did not reduce residual fade in human atrium in the presence of cilostamide. 5‐HT‐evoked increases in cAMP faded; fade was abolished by concurrent cilostamide + rolipram. Conclusions and implications:  PDE3‐induced control of porcine 5‐HT responses differed in atrium and ventricle and changed with age. PDE3 and PDE4 jointly prevented fade of inotropic and cAMP responses to 5‐HT in porcine atrium. Unlike porcine atria, only PDE3 induced fade of 5‐HT responses in human atria.
ISSN:0007-1188
1476-5381
DOI:10.1111/j.1476-5381.2008.00023.x