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Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium
- Source :
- Naunyn-Schmiedeberg's Archives of Pharmacology. 379:379-384
- Publication Year :
- 2008
- Publisher :
- Springer Science and Business Media LLC, 2008.
-
Abstract
- Acting through a low-affinity site of the beta(1)-adrenoceptor (beta(1L)AR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 microM) on the (-)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 +/- 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (-)-CGP12177 (-logEC(50)M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 +/- 9% of the effect of 200 microM (-)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (-)-CGP12177 (-logEC(50)M = 7.4) but concurrent rolipram + cilostamide caused potentiation (-logEC(50)M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the beta(1L)AR-induced cAMP compartment through which (-)-CGP12177 causes tachycardia. In contrast to the (-)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (-)-CGP12177-evoked increases of left atrial contractility through beta(1L)AR.
- Subjects :
- Male
Agonist
Chronotropic
Inotrope
medicine.medical_specialty
Phosphodiesterase Inhibitors
medicine.drug_class
Phosphodiesterase 3
Atrial Function, Right
In Vitro Techniques
Quinolones
Phosphodiesterase 3 Inhibitors
Propanolamines
Rats, Sprague-Dawley
Contractility
chemistry.chemical_compound
Heart Rate
Tachycardia
Internal medicine
Bradycardia
medicine
Animals
Arrhythmia, Sinus
Heart Atria
Rolipram
Pharmacology
Cilostamide
Atrium (architecture)
Isoproterenol
General Medicine
Adrenergic beta-Agonists
Myocardial Contraction
Cyclic Nucleotide Phosphodiesterases, Type 3
Stimulation, Chemical
Cyclic Nucleotide Phosphodiesterases, Type 4
Rats
Drug Partial Agonism
Endocrinology
chemistry
Adrenergic beta-1 Receptor Agonists
cardiovascular system
Atrial Function, Left
Female
Phosphodiesterase 4 Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 14321912 and 00281298
- Volume :
- 379
- Database :
- OpenAIRE
- Journal :
- Naunyn-Schmiedeberg's Archives of Pharmacology
- Accession number :
- edsair.doi.dedup.....621ddd7278cc9b3ecebf1a5c78998969