Effect of adenosine receptor ligands on cAMP content in human airways and peripheral lung.
Adenosine causes airway obstruction in asthmatics and smokers. Theophylline and cromolyn, drugs used to treat these patients, bind to human lung adenosine receptors (ARs). This study investigated whether A1ARs and/or A2ARs are functionally present in human lung and airways, and whether theophylline and/or cromolyn antagonize their function. Peripheral lung or airway fragments from 21 people were incubated for 15 min with (1) an A1AR agonist, N6-cyclopentyladenosine (CPA, 5 to 1,000 nM), or (2) an A2AR agonist, either 5'-N-ethylcarboxamido adenosine (NECA, 0.5 to 20 microM) or 2-[p-(2-carboxyethyl)-phenethyl amino]-5'-N-ethylcarboxamido adenosine (CGS 21680, 0.5 to 28 microM), in the presence of the A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (50 nM) and/or (3) theophylline (1 mM) and/or (4) cromolyn (500 microM). Adenosine deaminase (2 U/ml) and the phosphodiesterase inhibitor Ro 20-1724 (2 mM) were present in all incubations. Cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. In peripheral lung, CPA did not change baseline or isoproterenol-stimulated cAMP content. However, both NECA (20 microM) and CGS 21680 (28 microM) significantly (P < 0.05) increased cAMP content 220 +/- 4% and 201 +/- 32%, respectively (mean +/- SEM). In airways, 20 microM NECA increased cAMP content 129 +/- 34%, and 28 microM CGS 21680 increased it 52 +/- 20% (both P < 0.05). In both peripheral lung and airway tissue, NECA-induced increase in cAMP was antagonized by theophylline (P < 0.05) but not cromolyn. The lungs of younger, nonsmokers had lower baseline cAMP content but did not respond differentially to A2AR stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Joad
J P
JP
Department of Pediatrics, University of California, Davis.
Kott
K S
KS
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004205:Cromolyn Sodium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010627:Phenethylamines / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D008024:Ligands; D010627:Phenethylamines; D011983:Receptors, Purinergic; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000242:Cyclic AMP; D000241:Adenosine; D004205:Cromolyn Sodium