Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors - PubMed (original) (raw)

Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors

B K Kemp et al. Br J Pharmacol. 1999 Apr.

Abstract

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.

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Figures

Figure 1

Figure 1

Relaxations in human isolated small coronary arteries to (A) adenosine in normal Krebs' (control), high K+ (30 m

M

KCl) and a combination of oxyhaemoglobin (HbO) and

L

-NOARG (_n_=4–5), (B) adenosine in the presence of normal Krebs' (control, _n_=5) or glibenclamide (_n_=5) and (C) forskolin in normal Krebs' (control, _n_=4) and high K+ (_n_=4). Values are mean±s.e.mean. (*) indicates pEC50 value significantly different from control (P<0.05, Dunnett's modified _t_-statistic).

Figure 2

Figure 2

Relaxations to (A) the adenosine agonists; NECA, 2-CADO, adenosine, IB-MECA, R-PIA, CPA, S-PIA and CGS 21680 (_n_=4–5) and (B) adenosine in the absence (control) and presence of the adenosine antagonists, DPCPX, DMPX and 8-SPT (_n_=4–5) in human isolated small coronary arteries. Values are mean±s.e.mean. (*) indicates pEC50 value significantly different from control (P<0.01, Dunnett's modified _t_-statistic).

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