ADENOSINE RECEPTOR INTERACTIONS ALTER CARDIAC CONTRACTILITY IN THE RAT HEART.

The effect of an adenosine (Ado) A2 receptor agonist, N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA) on AdoA1 receptor mediated negative inotropic responses was investigated in rat heart. Hearts from male Wistar rats (250-350g) were perfused with Krebs-Henseleit solution at constant flow in non-recirculating Langendorff mode. Hearts were paced at 5 Hz (5 ms duration, supramaximal voltage) via ventricular electrodes. After 30 mins equilibration (R)-N6-phenylisopropyl adenosine (R-PIA) concentration-response curves were acquired in the absence or presence of DPMA. R-PIA induced concentration-dependent decreases in triple product (HR x left ventricular developed pressure x dP/dtmax) in paced hearts. DPMA (1 nM) significantly attenuated R-PIA induced decreases in triple product, with a shift in pEC50 from 8.0 ± 0.51 (n=9) in control hearts to 6.63 ± 1.03 (n=5) in treated tissues (P<0.05). The AdoA2AR antagonist 8-(3-chlorostyryl) caffeine (1 µM) and the adenylyl cyclase inhibitor cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL12330A, 100nM) reversed the effect of DPMA on AdoA1R mediated negative inotropic actions while the adoA2BR inhibitor (alloxazine, 3 µM) had no effect on DPMA activity. The results show that stimulation of AdoA2R attenuates AdoA1R dependent reductions in inotropic state. The adenosine receptor sub-type involved appears to be the AdoA2AR, and its action involves stimulation of adenylyl cyclase activity