Back to Search Start Over

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

Authors :
Faucher, Fabien A.
Gannier, Francois E.
Lignon, Jacques M.
Cosnay, Pierre
Malecot Claire O.
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