Bronchodilator activity of a nonxanthine phosphodiesterase inhibitor; 2,4-diamino-5-cyano-6-bromopyridine (compound I).
The ability of 2,4-diamino-5-cyano-6-bromopyridine (compound 1) to inhibit bronchiolar smooth muscle constriction was examined in isolated rings of rabbit primary bronchi and intrapulmonary bronchioles. After carbachol-induced constriction these tissue were significantly relaxed by either compound I or 1-methyl-3-isobutylxanthine (MIX) in a similar dose-dependent manner with 50 to 80% relaxation occurring at 100 microM of either compound. Compound I also attenuated the constrictor response of bronchial rings to histamine and significantly reduced the tension generated by horseradish peroxidase in sensitized tissues responding to this antigen. In addition, both compound I and MIX were found to inhibit the soluble cyclic AMP phosphodiesterase activity of rabbit bronchioles. Finally, both compound I and MIX caused a nearly 2-fold, time-dependent increase in cyclic AMP levels in isolated rabbit intrapulmonary bronchioles. The similarities of both the in vitro tissue responses to these compounds and the phosphodiesterase inhibitory properties suggest that the ability of compound I to reduce constrictor-induced tension generation in bronchial smooth muscle is related to the inhibition of cyclic nucleotide phosphodiesterases and the consequent elevation of cyclic AMP.
P F
PF
Smith
W J
WJ
Thompson
C
C
de Haën
M
M
Halonen
J D
JD
Palmer
D G
DG
Johnson
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015761:4-Aminopyridine / Q000031:analogs & derivatives*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors; D011817:Rabbits
D000631:Aminopyridines; D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; C041837:2,4-diamino-5-cyano-6-bromopyridine; D006632:Histamine; D002217:Carbachol; D015761:4-Aminopyridine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015056:1-Methyl-3-isobutylxanthine