Ontogenic changes of the control by phosphodiesterase-3 and -4 of 5-HT responses in porcine heart and relevance to human atrial 5-HT(4) receptors.

Abstract

BACKGROUND AND PURPOSE:

Atrial inotropic responses to 5-HT mediated through 5-HT(4) 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 micromol.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.

• Authors: Alejandro Galindo-Tovar, Maria Luisa Vargas, Elisa Escudero, Alberto J Kaumann
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 156 Issue 2 Pg. 237-49 (Jan 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19154438 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase 4 Inhibitors
• Quinolones
• Receptors, Serotonin, 5-HT4
• Serotonin
• cilostamide
• Cyclic AMP
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Cyclic Nucleotide Phosphodiesterases, Type 4
• Rolipram

Topics

• Age Factors
• Animals
• Animals, Newborn
• Arrhythmia, Sinus (physiopathology)
• Atrial Function (drug effects)
• Calcium Channels, L-Type (physiology)
• Cyclic AMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 3 (physiology)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (physiology)
• Dose-Response Relationship, Drug
• Female
• Heart Rate (drug effects)
• Humans
• In Vitro Techniques
• Male
• Middle Aged
• Muscle Contraction (drug effects)
• Myocytes, Cardiac (drug effects, physiology)
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase 4 Inhibitors
• Quinolones (pharmacology)
• Receptors, Serotonin, 5-HT4 (physiology)
• Rolipram (pharmacology)
• Serotonin (pharmacology)
• Species Specificity
• Swine
• Ventricular Function (drug effects)