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RECEPTORS AND SIGNAL TRANSDUCTION

Roles of PKA, PI3K, and cPLA₂ in the NO-mediated negative inotropic effect of β₂-adrenoceptor agonists in guinea pig right papillary muscles

Centre National de la Recherche Scientifique UMR 6542, Physiologie des Cellules Cardiaques et Vasculaires, Faculté des Sciences, Université François-Rabelais, Tours, France

Submitted 1 June 2007 ; accepted in final form 16 October 2007

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 (G_s/G_i coupled and G_i 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.

salbutamol; β-adrenoceptor antagonists; cardiac contractility; G_s/-G_i coupling; active conformations