Abstract
The objectives of this study were to investigate the mechanism underlying the adenosine A2a receptor (A2aR)-mediated positive inotropic response and to define its contractile function using chick embryo ventricular cells as a model. Activation of the A2aR caused a marked stimulation of calcium entry and cell contractility, which were blocked by verapamil or nifedipine. The effects elicited by maximal concentrations of the A2aR agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine and the beta-adrenergic agonist isoproterenol were additive, indicating that the two receptors do not share a common stimulatory mechanism. The cAMP antagonist (Rp)-adenosine cyclic 3':5'-monophosphorothioate was ineffective in inhibiting the A2aR-mediated stimulation of contractility or the L-type calcium channel, while it completely abolished the isoproterenol effects. Activation of the A2aR had no effect on Na+/Ca2+ exchange or inositol 1,4,5-trisphosphate accumulation. Blocking of the A2aR resulted in unopposed A1 receptor-mediated inhibitory effects and led to an inhibition of basal contractility and an enhanced anti-adrenergic effect by A1 agonist. The adenosine A2a receptor mediates a new cyclic AMP-independent mechanism and a new contractile function in the cardiac cell.
Highlights
A2a receptor (A2aR)-mediated stimulation of contractility or the L-type calcium channel, while it completely abolished the isoproterenol effects
In cells where the A1 receptor was first inactivated by prior treatment with pertussis toxin, the A2a receptor-selective agonist CGS21680 caused a marked increase in myocyte contractile amplitude that was additive to the increase elicited by maximally effective concentration of the -adrenergic agonist isoproterenol (Fig. 1A), indicating that the two receptor pathways do not share a common mechanism of positive inotropic response
Previous studies carried out in this laboratory have demonstrated the existence of a high affinity adenosine A2a receptor capable of mediating a marked positive inotropic response in cultured fetal chick embryo ventricular cells [14, 15]
Summary
A2aR-mediated stimulation of contractility or the L-type calcium channel, while it completely abolished the isoproterenol effects. The objectives of this study, using cultured fetal ventricular cells as a model system, were to investigate the mechanism underlying the adenosine A2a receptor-mediated positive inotropic response and to study the contractile function subserved by the A2a receptor. The ␣-adrenergic receptor-medicium entry; that a cyclic AMP-independent, Gs-mediated mechanism is largely responsible for the A2a receptor-mediated stimulatory response; and that a physiological action of the ated augmentation of cardiac contractility involves stimulation activated A2a receptor is to oppose the inhibitory effect of A1 by inositol phosphates and protein kinase C that is cyclic AMP- receptor agonist on basal and -adrenergic stimulated conindependent [5,6,7,8]. Using fetal chick embryo ventricular cells as a model, prior studies demonstrated the presence of a high affin-
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