Abstract
Adenosine, an important signaling molecule in asthma, produces bronchoconstriction in asthmatics. Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating A1 adenosine receptors (ARs). Effects of L-97-1 [3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxyethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione] a water-soluble, small molecule A1 AR antagonist were investigated on early and late phase allergic responses (EAR and LAR) in a hyper-responsive rabbit model of asthma. Rabbits were made allergic by intraperitoneal injections of house dust mite [HDM; 312 allergen units (AU)] extract within 24 h of their birth. Booster HDM injections were given weekly for 1 month, biweekly for 4 months, and continued monthly thereafter. Hyperresponsiveness was monitored by measuring lung dynamic compliance (Cdyn), after histamine or adenosine aerosol challenge in allergic rabbits. Hyper-responsive rabbits were subjected to aerosol of HDM (2500 AU), 1 h after intragastric administration of L-97-1 (10 mg/kg) solution or an equivalent volume of saline. Cdyn was significantly higher after treatment with L-97-1 compared with untreated controls (p < 0.05 n = 5). Histamine PC30 was significantly higher (p < 0.05; n = 5) after L-97-1 at 24 h compared with histamine PC30 at 24 h after HDM. Adenosine PC30 was significantly higher at 15 min and 6 h after L-97-1 compared with control (p < 0.05; n = 5). L-97-1 showed strong affinity for human A1 ARs in radioligand binding studies and no inhibition toward human phosphodiesterase II, III, IV, and V enzymes. These data suggest that L-97-1 produces a significant reduction of histamine or adenosine-induced hyper-responsiveness and HDM-induced EAR and LAR in allergic rabbits by blocking A1 ARs and may be beneficial as an oral therapy for human asthma.
Footnotes
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This study was supported by North Carolina Biotechnology Center Kenan Award Collaborative Funding Assistance 2000 Collaborative Funding Grant 8002 and Small Business Technology Transfer Phase I Grant HL070458.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.088179.
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ABBREVIATIONS: AR, adenosine receptor; L-97-1, 3-[2-(4-aminophenyl)-ethyl]-8-benzyl-7-{2-ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-1-propyl-3,7-dihydro-purine-2,6-dione; HDM, house dust mite; EAR, early allergic response; LAR, late allergic response; AU, allergen unit; Cdyn, dynamic compliance; BHR, bronchial hyper-responsiveness; 2-CADO, 2-chloroadenosine; PAEC, pulmonary artery endothelial cell; NMDA, N-methyl-d-aspartate; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; CGS 21680, 2-[p-(2-carboxyethyl)phenethylamino]-5′-N-ethylcarboxamidoadenosine; ANOVA, analysis of variance; MANOVA, multiple analysis of variance; PDE, phosphodiesterase; ASM, airway smooth muscle.
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↵1 Current address: Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, WV.
- Received April 19, 2005.
- Accepted July 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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