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Contractile effects of adenosine A₁ and A_2A receptors in isolated murine hearts

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

Submitted 13 July 2005 ; accepted in final form 30 August 2005

The adenosine A₁ receptor (A₁R) inhibits -adrenergic-induced contractile effects (antiadrenergic action), and the adenosine A_2A receptor (A_2AR) both opposes the A₁R action and enhances contractility in the heart. This study investigated the A₁R and A_2AR function in -adrenergic-stimulated, isolated wild-type and A_2AR 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. A₁R activation with 2-chloro-N⁶-cyclopentyladenosine (CCPA) resulted in a 27% reduction in contractile response to the -adrenergic agonist isoproterenol (ISO). Stimulation of A_2AR 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_2AR were absent in knockout hearts. Up to 63% of the A_2AR influence was estimated to be mediated through its inhibition of the A₁R antiadrenergic effect, with the remainder being the direct contractile effect. Further experiments examined the effects of A_2AR activation and associated vasodilation with low-flow ischemia in the absence of -adrenergic stimulation. A_2AR 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_2AR 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, A₁R and A_2AR modulate the response to -adrenergic stimulation with A_2AR, attenuating the effects of A₁R and also increasing contractility directly. In addition, A_2AR supports myocardial contractility in a setting of low-flow ischemia.

perfused heart; antiadrenergic; cardiac contractility; adenosine A_2A knockout; chlorocyclopentyladenosine; CGS-21680; ischemia

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