PROLONGED EXPOSURE TO 5′-N-ETHYLCARBOXAMIDOADENOSINE (NECA) DOES NOT AFFECT THE ADENOSINE A2A-MEDIATED VASODILATION IN PORCINE CORONARY ARTERIES

Abstract

At present, four distinct adenosine receptors (A1, A2A, A2B, and A3) have been cloned and characterized in several species. It is known that prolonged exposure of tissues to receptor agonists induces A1receptor desensitization. However, controversial data are reported on whether or not prolonged stimulation of A2Aadenosine receptors induces tolerance. Using the porcine coronary artery, a sensitive vascular model, studies were designed, with the aim to clarify how prolonged exposure to the adenosine agonist 5′-N-ethylcarboxamidoadenosine (NECA) affects A2Areceptor responsiveness. The arteries were precontracted with PGF2α(3gmM) and cumulative dose-response curves to either NECA itself, or the selective A2Aagonists, 2-[4-2(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine (CGS 21680) and 2-hexynyl-5′-N-ethylcarboxamidoadenosine (2HE-NECA) were obtained. In separate experiments, coronary rings were incubated with NECA (10gmM) for 30min or 2h. After 2h washout period, functional response was assessed.The arteries showed high sensitivity to adenosine agonist-induced vasorelaxation.EC50(nM) values were 71.8 (35.5–145), 20.0 (11.2–32.7) and 40.2 (20.4–79.1) for NECA, 2HE-NECA and CGS 21680, respectively. Vasorelaxant response of A2Aselective agonists 2HE-NECA and CGS 21680 was not influenced by preincubation with NECA for 30min or 2h. Conversely, dose-response curves to NECA were shifted toward the right by preincubation with NECA itself: ED50(nM) values were 114 (79.2–165), 211 (161–276) and 412 (132–1290) for 30min, 2h and 15h preincubation, respectively. These effects did not occur after 4h washout. The present results indicate that prolonged stimulation of A2Areceptors does not lead to loss of functional response, suggesting that this receptor subtype does not desensitize after prolonged stimulation by agonists.