Adenosine A_2a-receptor activation increases contractility in isolated perfused hearts

Abstract

Adenosine A(2a)-receptor activation enhances shortening of isolated cardiomyocytes. In the present study the effect of A(2a)-receptor activation on the contractile performance of isolated rat hearts was investigated by recording left ventricular pressure (LVP) and the maximal rate of LVP development (+dP/dt(max)). With constant-pressure perfusion, adenosine caused concentration-dependent increases in LVP and +dP/dt(max), with detectable increases of 4.1 and 4.8% at 10(-6) M and maximal increases of 12.0 and 11.1% at 10(-4) M, respectively. The contractile responses were prevented by the A(2a)-receptor antagonists chlorostyryl-caffeine and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385) but were not affected by the beta(1)-adrenergic antagonist atenolol. The adenosine A(1)-receptor antagonist dipropylcyclopentylxanthine and pertussis toxin potentiated the positive inotropic effects of adenosine. The A(2a)-receptor agonists ethylcarboxamidoadenosine and dimethoxyphenyl-methylphenylethyl-adenosine also enhanced contractility. With constant-flow perfusion, 10(-5) M adenosine increased LVP and +dP/dt(max) by 5.5 and 6.0%, respectively. In the presence of the coronary vasodilator hydralazine, adenosine increased LVP and +dP/dt(max) by 7.5 and 7.4%, respectively. Dipropylcyclopentylxanthine potentiated the adenosine contractile responses with constant-flow perfusion in the absence and presence of hydralazine. These increases in contractile performance were also antagonized by chlorostyryl-caffeine and ZM-241385. The results indicate that adenosine increases contractile performance via activation of A(2a) receptors in the intact heart independent of beta(1)-adrenergic receptor activation or changes in coronary flow.

Adenosine A2Aand β-adrenergic calcium transient and contractile responses in rat ventricular myocytes

“…However, it is now shown that maximal velocities of Ca transient ratio increase and recovery are also increased upon A 2A R stimulation. The concentration of the A 2A R agonist CGS-21680 employed in this study is similar to the concentrations used in previous reports for perfused hearts (32,42) and ventricular myocytes (12,29). Although equilibrium-binding studies in the brain indicate that the inhibition constant K i for CGS-21680 is ϳ30 nM (21), generally higher concentrations of the agonist are required to observe a myocyte response within several minutes as performed above.…”

“…This naturally occurring nucleoside in the myocardium (8,16) is capable of interacting with both the adenosine A 2A receptor (A 2A R) and adenosine A 1 receptor (A 1 R) to modulate contractile function. The A 2A R have been reported to increase contractile performance in rat (12) and neonatal avian (29) ventricular myocytes as well as increase the contractility of perfused rat (32) and mouse (42) hearts. A 2A R have been postulated to activate adenylyl cyclase (29) or initiate mechanisms that are Ca dependent and -independent (11,44) and cAMP independent (12,30).…”

Effect of K + ATP Channel and Adenosine Receptor Blockade During Rest and Exercise in Congestive Heart Failure

“…26 Because cardiac energy use appears to be downregulated in CHF, whereas adenosine production is increased, it is possible that adenosine may modulate metabolism in the failing heart through antiadrenergic effects on A 1 receptors or through inhibition of mitochondrial respiration via NO.…”

Adenosine A1Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

“…Another conceivable mechanism whereby A 1 AdoR selective antagonism may increase cardiac output during hypoxia is allowing unopposed direct cardiac stimulation mediated by the A 2 AdoR (A 2a subtype). 17 Rapid, severe hypoxia is the primary problem in patients with certain insults (e.g., massive carbon monoxide exposure, near-drowning) and is a major contributing problem in others (e.g., acute airway obstruction, cardiac arrest). In these and in other lowflow states (e.g., hemorrhagic shock), impairments in systemic oxygenation or perfusion impair myocardial perfusion or oxygenation; endogenous Ado levels increase, presumably contributing to cardiac insufficiency.…”