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Roles of PKA, PI3K, and [cPLA.sub.2] in the NO-mediated negative inotropic effect of [[beta].sub.2]-adrenoceptor agonists in guinea pig right papillary muscles
- Source :
- The American Journal of Physiology. Jan, 2008, Vol. 294 Issue 1, pC106, 12 p.
- Publication Year :
- 2008
-
Abstract
- Although [[beta].sub.2]-adrenoceptors represent 15-25% of [beta]-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of [[beta].sub.2]-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 [micro]M) due to activation of [[beta].sub.1]-adrenoceptors. In the presence of 4 [micro]M atenolol, the concentration-dependent NIE (- 12% at 6 [micro]M) was biphasic, best described by a double logistic equation with respective [EC.sub.50] 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 [A.sub.2] ([cPLA.sub.2]) 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 [cPLA.sub.2]. The possibility that these effects are due to an equilibrium between different affinity states of the receptor ([G.sub.s]/[G.sub.i] coupled and [G.sub.i] independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that [[beta].sub.2]-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state. salbutamol; [beta]-adrenoceptor antagonists; cardiac contractility; [G.sub.s]/ -[G.sub.i] coupling; active conformations
Details
- Language :
- English
- ISSN :
- 00029513
- Volume :
- 294
- Issue :
- 1
- Database :
- Gale General OneFile
- Journal :
- The American Journal of Physiology
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.174323549