Adenosine mediates relaxation of human small resistance‐like coronary arteries via A 2B receptors

The receptor subtype and mechanisms underlying relaxation to adenosine were examined in human isolated small coronary arteries contracted with the thromboxane A 2 mimetic, 1,5,5‐hydroxy‐11α, 9α‐(epoxymethano)prosta‐5Z, 13E‐dienoic acid (U46619) to approximately 50% of their maximum contraction to K + (125 m M ) depolarization (F max ). Relaxations were normalized as percentages of the 50% F max contraction. Adenosine caused concentration‐dependent relaxations (pEC 50 , 5.95±0.20; maximum relaxation (R max ), 96.7±1.4%) that were unaffected by either combined treatment with the nitric oxide inhibitors, N G ‐nitro‐ L ‐arginine ( L ‐NOARG; 100 μ M ) and oxyhaemoglobin (HbO; 20 μ M ) or the ATP‐dependent K + channel (K ATP ) inhibitor, glibenclamide (10 μ M ). The pEC 50 but not R max to adenosine was significantly reduced by high extracellular K + (30 m M ). Relaxations to the adenylate cyclase activator, forskolin, however, were unaffected by high K + (30 m M ). Adenosine and a range of adenosine analogues, adenosine, 2‐chloroadenosine (2‐CADO), 5′‐N‐ethyl‐carboxamidoadenosine (NECA), R(−)‐N 6 ‐(2‐phenylisopropyl)‐adenosine (R‐PIA), S(+)‐N 6 ‐(2‐phenylisopropyl)‐adenosine (S‐PIA), N 6 ‐cyclopentyladenosine (CPA), 1‐deoxy‐1‐[6‐[[(3‐iodophenyl)methyl]amino]‐9H‐purin‐9‐yl]‐N‐methyl‐β‐ D ‐ribofuranuronamide (IB‐MECA), 2‐ p ‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamido adenosine hydrochloride (CGS 21680), relaxed arteries with a rank order of potency of NECA=2‐CADO>adenosine=IB‐MECA=R‐PIA= CPA>S‐PIA)>CGS 21680. Sensitivity but not R max to adenosine was significantly reduced approximately 80 and 20 fold by the non‐selective adenosine receptor antagonist, 8‐(p‐sulphophenyl)theophylline (8‐SPT) and the A 2 receptor antagonist, 3,7‐dimethyl‐1‐propargylxanthine (DMPX). By contrast, the A 1 ‐selective antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) had no effect on pEC 50 or R max to adenosine. These results suggest that A 2B receptors mediate relaxation to adenosine in human small coronary arteries which is independent of NO but dependent in part on a K + ‐sensitive mechanism.British Journal of Pharmacology (1999) 126 , 1796–1800; doi: 10.1038/sj.bjp.0702462