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.
OBJECTIVE
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.


METHODS
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.


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
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.
Galindo-Tovar
Alejandro
A
Department of Pharmacology, Medical School, Murcia, Spain.
Vargas
Maria Luisa
ML
Escudero
Elisa
E
Kaumann
Alberto J
AJ
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001146:Arrhythmia, Sinus / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones / Q000494:pharmacology; D044422:Receptors, Serotonin, 5-HT4 / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine; D016276:Ventricular Function / Q000187:drug effects
D020746:Calcium Channels, L-Type; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; C021294:cilostamide; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram