Loss of vascular adenosine A1 receptors with age in the rat heart

Abstract: Objective: To investigate the effects of age on adenosine A1 receptor (ADORA1) mediated vascular, inotropic and chronotropic functional responses in isolated rat hearts. Methods: NECA (5′-(N-ethylcarboxamido)adenosine) and R-PIA (R-N 6-(1-methyl-2-phenylethyl)adenosine) concentration–response curves were produced in Langendorff prepared hearts isolated from immature (6 weeks), young (16 weeks) and mature (52 weeks) male Wistar rats and the effects of DPCPX (ADORA1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, 30 nM) and pertussis toxin pre-treatment (PTX, 48 h, 10 μg/kg IP, inhibits Gi/o-protein) were observed. Results: NECA mediated coronary vasodilation and induced biphasic concentration–response curves in hearts from immature rats (pEC50 8.5 (8.1–8.9) and 11.3 (10.3–12.3)). At the low sensitivity site, the potency of NECA increased in young but not mature rats and remained unchanged at the high sensitivity site. Both DPCPX and PTX each blocked NECA at the high sensitivity site in immature rats, producing monophasic concentration–response curves (pEC50 8.6 (8.5–9.9) for DPCPX and pEC50 8.7 (8.3–9.0) for PTX), but not in young and mature rats. A vasoconstrictor response was observed at low NECA concentrations in hearts from PTX pre-treated immature rats, but not in hearts from young and mature rats, and the response was inhibited by DPCPX. No age related changes were observed in R-PIA mediated negative inotropic and chronotropic responses (P >0.05). Conclusion: ADORA1 mediates a vasodilator response as well as a vasoconstrictor response in the coronary resistance vessels; the latter occurs via a PTX-insensitive pathway and declines with age. [Copyright &y& Elsevier]