A novel adenosine analog, AMP579, inhibits neutrophil activation, adherence and neutrophil-mediated injury to coronary vascular endothelium.
We hypothesized that 1S-[1a,2b,3b, 4a(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methylpropyl]propyl-amino]-3H-i midazo[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/20x10(6) neutrophils) from platelet activating factor (PAF)-activated neutrophil in concentration-dependent manner (4.1+/-0.8 at 10 microM vs. 16.7+/-2.1 in PAF group, P<0.05). This inhibitory effect was blocked by the adenosine A(2A) 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 microM (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 microM). A total of 10 microM 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 A(2A) receptor mechanism.
Nakamura
M
M
Department of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, GA 30365, USA.
Zhao
Z Q
ZQ
Clark
K L
KL
Velez
D V
DV
Guyton
R A
RA
Vinten-Johansen
J
J
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D015550:Cell Degranulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D007093:Imidazoles; D011725:Pyridines; D011799:Quinazolines; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; D013481:Superoxides; C051360:1,3-dipropyl-8-cyclopentylxanthine