Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors.
1. The receptor subtype and mechanisms underlying relaxation to adenosine were examined in human isolated small coronary arteries contracted with the thromboxane A2 mimetic, 1,5,5-hydroxy-11alpha, 9alpha-(epoxymethano)prosta-5Z, 13E-dienoic acid (U46619) to approximately 50% of their maximum contraction to K+ (125 mM) depolarization (Fmax). Relaxations were normalized as percentages of the 50% Fmax contraction. 2. Adenosine caused concentration-dependent relaxations (pEC50, 5.95+/-0.20; maximum relaxation (Rmax), 96.7+/-1.4%) that were unaffected by either combined treatment with the nitric oxide inhibitors, NG-nitro-L-arginine (L-NOARG; 100 microM) and oxyhaemoglobin (HbO; 20 microM) or the ATP-dependent K+ channel (KATP) inhibitor, glibenclamide (10 microM). The pEC50 but not Rmax to adenosine was significantly reduced by high extracellular K+ (30 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-chloroadenosine (2-CADO), 5'-N-ethyl-carboxamidoadenosine (NECA), R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA), S(+)-N6-(2-phenylisopropyl)-adenosine (S-PIA), N6-cyclopentyladenosine (CPA), 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- 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. 4. Sensitivity but not Rmax 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 A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). By contrast, the A1-selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) had no effect on pEC50 or Rmax to adenosine. 5. These results suggest that A2B receptors mediate relaxation to adenosine in human small coronary arteries which is independent of NO but dependent in part on a K+-sensitive mechanism.
Kemp
B K
BK
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
Cocks
T M
TM
D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D000368:Aged; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000008:administration & dosage / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010108:Oxyhemoglobins; D015221:Potassium Channels; D058915:Purinergic P1 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D000241:Adenosine; D011188:Potassium