Prolonged exposure to 5'-N-ethylcarboxamidoadenosine (NECA) does not affect the adenosine A(2A)-mediated vasodilation in porcine coronary arteries

At present, four distinct adenosine receptors (A(1), A(2A), A(2B), and A(3)) have been cloned and characterized in several species. It is known that prolonged exposure of tissues to receptor agonists induces A(1) receptor desensitization. However, controversial data are reported on whether or not prolonged stimulation of A(2A) adenosine 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 adeno sine agonist 5'-N-ethylcarboxamidoadenosine (NECA) affects A(2A) receptor responsiveness. The arteries were precontracted with PGF(2 alpha) (3 mu M) and cumulative dose-response curves to either NECA itself, or the selective A(2A) agonists, 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 (10 mu M) for 30 min or 2 h. After 2 h 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 A(2A) selective agonists 2HE-NECA and CGS 21680 was not influenced by preincubation with NECA for 30 min or 2 h. 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 30 min, 2 h and 15 h preincubation, respectively. These effects did not occur after 4 h washout. The present results indicate that prolonged stimulation of A(2A) receptors does not lead to loss of functional response, suggesting that this receptor subtype does not desensitize after prolonged stimulation by agonists. (C) 1997 The Italian Pharmacological Society.