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Roles of PKA, PI3K, and cPLA2 in the NO-mediated negative inotropic effect of β2-adrenoceptor agonists in guinea pig right papillary muscles
- Source :
- American Journal of Physiology-Cell Physiology. 294:C106-C117
- Publication Year :
- 2008
- Publisher :
- American Physiological Society, 2008.
-
Abstract
- Although β2-adrenoceptors represent 15–25% of β-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of β2-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, −5% at 60 nM) followed by a moderate positive inotropic effect (+36% at 6 μM) due to activation of β1-adrenoceptors. In the presence of 4 μM atenolol, the concentration-dependent NIE (−12% at 6 μM) was biphasic, best described by a double logistic equation with respective EC50 values of 3 and ∼420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/cytosolic phospholipase A2 (cPLA2) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA2. The possibility that these effects are due to an equilibrium between different affinity states of the receptor (Gs/Gi coupled and Gi independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that β2-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.
- Subjects :
- Male
Inotrope
medicine.medical_specialty
Adrenergic receptor
Physiology
Adrenergic beta-Antagonists
Guinea Pigs
GTP-Binding Protein alpha Subunits, Gi-Go
In Vitro Techniques
Nitric Oxide
Partial agonist
Nitric oxide
Propanolamines
Guinea pig
Contractility
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Catecholamines
Internal medicine
medicine
Animals
Albuterol
Phosphorylation
Adrenergic beta-2 Receptor Agonists
Arachidonic Acid
Dose-Response Relationship, Drug
Chemistry
Group IV Phospholipases A2
Antagonist
Cell Biology
Adrenergic beta-Agonists
Papillary Muscles
Cyclic AMP-Dependent Protein Kinases
Myocardial Contraction
Phosphoric Monoester Hydrolases
Drug Partial Agonism
Endocrinology
Atenolol
Adrenergic beta-1 Receptor Agonists
Prostaglandin-Endoperoxide Synthases
Depression, Chemical
Receptors, Adrenergic, beta-2
Receptors, Adrenergic, beta-1
Signal Transduction
Subjects
Details
- ISSN :
- 15221563 and 03636143
- Volume :
- 294
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Cell Physiology
- Accession number :
- edsair.doi.dedup.....8211fdb358ee65bb9cee69264d7959a9