A novel adenosine analog, AMP579, inhibits neutrophil activation, adherence and neutrophil-mediated injury to coronary vascular endothelium

We hypothesized that I S-[1a,2b,3b,4a(S *)]-4-[7-[[1-[(3-chloro-2-thienyl)methylpropyl]propyl]-amino]3H-imidazo[4,5-b] pyridyl-3-yl]-N-ethyl-2,3-dihydroxycyclopentane carboxamide (AMP579), a new adenosine analog, inhibits superoxide anion (O-2(-)) generation and degranulation from canine neutrophils, neutrophil adherence and neutrophil-induced dysfunction to canine coronary artery endothelium by adenosine receptor-mediated mechanisms. AMP579 inhibited O-2(-) generation(nM/20 x 10(6) neutrophils) from platelet activating factor (PAF)-activated neutrophil in concentration-dependent manner (4.1 +/- 0.8 at 10 mu M VS. 16.7 +/- 2.1 in PAF group, P < 0.05). This inhibitory effect was blocked by the adenosine A,, receptor-selective antagonist, 4-(2-[7-Amino-2-(2-furyl)[ 1,2,4]triazolo[2,3 -a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385, 17.7 +/- 2.8, P < 0.05), but not by either the adenosine A(1) receptor-selective antagonist, 8-Cyclopentyl-1.3-dipropylxanthine (DPCPX) or the adenosine A(3) receptor-selective antagonist, 9-Chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][ 1,2,4]-triazolo[1,5-c]quinazoline (MRS1220). AMP579 inhibited neutrophil degranulation dose-dependently by 38 +/- 2% at 10 mu M (P < 0.05). The inhibitory effect of AMP579 was not altered by either DPCPX or MRS1220, but was partially reversed by ZM241385 (69 +/- 8%, P < 0.05 vs. AMP579 10 mu M) A total of 10 mu M AMP579 reduced neutrophil adherence to thrombin-stimulated endothelium (neutrophils/mm(2)) from 269 +/- 16 to 44 +/- 4 (P < 0.05); this was reversed by ZM241385, but not by DPCPX or MRS1220. After coincubation of unstimulated neutrophil with thrombin-stimulated endothelium, concentration-relaxation responses to the endothelium receptor-dependent vasodilator, acetylcholine, were reduced (maximum 57 +/- 5% vs. 120 +/- 5% in controls, P < 0.05). This endothelial dysfunction was attenuated by AMP579 (116 +/- 7%, P < 0.05). We conclude that AMP579 inhibits neutrophil activation and neutrophil-mediated coronary endothelial dysfunction, primarily by an adenosine AZA receptor mechanism. (C) 2000 Elsevier Science B.V. Al rights reserved.