Adenosine A2a-receptor activation enhances cardiomyocyte shortening via Ca2+-independent and -dependent mechanisms

Abstract

Adenosine A2a receptor (A2aR) stimulation enhances the shortening of ventricular myocytes. Whether the A2aR-mediated increase in myocyte contractility is associated with alterations in the amplitude of intracellular Ca2+ transients was investigated in isolated, contracting rat ventricular myocytes using the Ca2+-sensitive fluorescent dye fura 2-AM. In the presence of intact inhibitory G protein pathways, 10−4 M 2- p-(2-carboxyethyl)phenethyl-amino-5′- N-ethylcarboxamidoadenosine (CGS-21680), an A2aR agonist, insignificantly increased Ca2+transients by 8 ± 5%, whereas myocyte shortening increased by 54 ± 1%. In contrast, 2 × 10−7 M isoproterenol, a β-adrenergic receptor agonist, increased Ca2+ transients by 104 ± 15% and increased myocyte shortening by 61 ± 6%. When A2aR were stimulated in myocytes that had the antiadrenergic actions of adenosine (Ado) abolished by either treatment with pertussis toxin (PTx) or the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1-receptor antagonist, the maximum increases in Ca2+transients were similarly nominal (with PTx: 10−4 M CGS-21680, 14 ± 6% and 10−4 M Ado, 15 ± 4%; without PTx: 10−5 M Ado + 2 × 10−7 M DPCPX, 19 ± 1%). These results indicate that compared with β-adrenergic stimulation, which markedly increases myocyte Ca2+ transients and shortening, A2aR-mediated increases in myocyte shortening are accompanied by only modest increases in Ca2+ transients. These observations suggest that the A2aR-induced contractile effects are mediated predominantly by Ca2+-independent inotropic mechanisms.