Adenosine mediates relaxation of human small resistance-like coronary arteries via A(2B) receptors

1 The receptor subtype and mechanisms underlying relaxation to adenosine we re examined in human isolated small coronary arteries contracted with the t hromboxane A(2) mimetic, 1,5,5-hydroxy-11 alpha, 9 alpha-(epoxymethano)pros ta-5Z, 13E-dienoic acid (U46619) to approximately 50% of their maximum cont raction to K+ (125 mM) depolarization (F-max). Relaxations were normalized as percentages of the 50% F-max contraction. 2 Adenosine caused concentration-dependent relaxations (pEC(50), 5.95 +/- 0 .20; maximum relaxation (R-max), 96.7 +/- 1.4%) that were unaffected by eit her combined treatment with the nitric oxide inhibitors, N-G-nitro-L-argini ne (L-NOARG; 100 mu M) and oxyhaemoglobin (HbO: 20 mu M) or the ATP-depende nt K+ channel (K-ATP) inhibitor, glibenclamide (10 mu M). The pEC(50) but n ot R-max to adenosine was significantly reduced by high extracellular K+ (3 0 mM). Relaxations to the adenylate cyclase activator, forskolin, however, were unaffected by high K+ (30 mM). 3 Adenosine and a range of adenosine analogues, adenosine, 2-chloroadenosin e (2-CADO), 5'-N-ethyl-carboxamidoodenosine (NECA), R(-)-N-6-(2-phenylisopr opyl)-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-beta-D-ribofuranuronamide (IB-MECA), 2-p-(2-carboxyet hyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680 ), relaxed arteries with a rank order of potency of NECA = 2-CADO > adenosi nse = IB-MECA = R-PIA = CPA > S-PIA) > CGS 21680. 4 Sensitivity but not R-max to adenosine was significantly reduced approxim ately 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 antago nist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) had no effect on pEC(50) o r R-max to adenosine. 5 These results suggest that A(2B) receptors mediate relaxation to adenosin e in human small coronary arteries which is independent of NO but dependent in part on a K+-sensitive mechanism.