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Adenosine A_2A and β-adrenergic calcium transient and contractile responses in rat ventricular myocytes

Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 22 August 2008 ; accepted in final form 6 October 2008

The adenosine A_2A receptor (A_2AR) enhances cardiac contractility, and the adenosine A₁R receptor (A₁R) is antiadrenergic by reducing the adrenergic β₁ receptor (β₁R)-elicited increase in contractility. In this study we compared the A_2AR-, A₁R-, and β₁R-elicited actions on isolated rat ventricular myocytes in terms of Ca transient and contractile responses involving PKA and PKC. Stimulation of A_2AR with 2 µM (EC₅₀) CGS-21680 (CGS) produced a 17–28% increase in the Ca transient ratio (CTR) and maximum velocities (V_max) of transient ratio increase (+MVT) and recovery (–MVT) but no change in the time-to-50% recovery (TTR). CGS increased myocyte sarcomere shortening (MSS) and the maximum velocities of shortening (+MVS) and relaxation (–MVS) by 31–34% with no change in time-to-50% relengthening (TTL). β₁R stimulation using 2 nM (EC₅₀) isoproterenol (Iso) increased CTR, +MVT, and –MVT by 67–162% and decreased TTR by 43%. Iso increased MSS, +MVS, and –MVS by 153–174% and decreased TTL by 31%. The A_2AR and β₁R Ca transient and contractile responses were not additive. The PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamonium salt prevented both the CGS- and Iso-elicited contractile responses. The PKC inhibitors chelerythrine and KIE1-1 peptide (PKC specific) prevented the antiadrenergic action of A₁R but did not influence A_2AR-mediated increases in contractile variables. The findings suggest that cardiac A_2AR utilize cAMP/PKA like β₁R, but the Ca transient and contractile responses are less in magnitude and not equally affected. Although PKC is important in the A₁R antiadrenergic action, it does not seem to play a role in A_2AR-elicited Ca transient and contractile events.

adenosine A₁ receptor; contractility; protein kinase A; protein kinase C; sarcomere shortening