Contractile effects of adenosine A1 and A2A receptors in isolated murine hearts

Contractile effects of adenosine A(1) and A(2A) receptors in isolated murine hearts. Am J Physiol Heart Circ Physiol 290: H348 - H356, 2006. First published September 2, 2005; doi: 10.1152/ajpheart. 00740.2005. The adenosine A(1) receptor (A(1)R) inhibits beta-adrenergic-induced contractile effects (antiadrenergic action), and the adenosine A(2A) receptor (A(2A)R) both opposes the A(1)R action and enhances contractility in the heart. This study investigated the A(1)R and A(2A)R function in beta-adrenergic-stimulated, isolated wild-type and A(2A)R knockout murine hearts. Constant flow and pressure perfused preparations were employed, and the maximal rate of left ventricular pressure (LVP) development (+dp/dt(max)) was used as an index of cardiac function. A(1)R activation with 2-chloro-N-6-cyclopentyladenosine (CCPA) resulted in a 27% reduction in contractile response to the beta-adrenergic agonist isoproterenol (ISO). Stimulation of A(2A)R with 2-P(2-carboxyethyl) phenethyl-amino-5'-N-ethylcarboxyamidoadenosine (CGS- 21680) attenuated this antiadrenergic effect, resulting in a partial ( constant flow preparation) or complete ( constant pressure preparation) restoration of the ISO contractile response. These effects of A(2A)R were absent in knockout hearts. Up to 63% of the A(2A)R influence was estimated to be mediated through its inhibition of the A(1)R antiadrenergic effect, with the remainder being the direct contractile effect. Further experiments examined the effects of A(2A)R activation and associated vasodilation with low-flow ischemia in the absence of beta-adrenergic stimulation. A(2A)R activation reduced by 5% the depression of contractile function caused by the flow reduction and also increased contractile performance over a wide range of perfusion flows. This effect was prevented by the A(2A)R antagonist 4-(2-[7-amino- 2-(2-furyl)[1,2,4] triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol (ZM- 241385). It is concluded that in the murine heart, A(1)R and A2AR modulate the response to beta-adrenergic stimulation with A(2A)R, attenuating the effects of A(1)R and also increasing contractility directly. In addition, A(2A)R supports myocardial contractility in a setting of low-flow ischemia.