Antibronchoconstrictor activity of two new phosphodiesterase inhibitors, a triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197)

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Abstract
A triazolopyrazine (ICI 58 301) and a triazolopyrimidine (ICI 63 197), both potent inhibitors of 3′5′-cyclic adenosine monophosphate phosphodiesterase, protected conscious guinea-pigs against an otherwise lethal bronchospasm caused by inhalation of histamine. Both compounds were active when given by mouth and the activity was both rapid in onset and persistent. Bronchospasm caused by histamine or acetylcholine in guinea-pig isolated lungs was reduced when the lungs were perfused with dilute solutions of the compounds and the bronchodilator activity of catecholamines was potentiated. In anaesthetized animals the compounds were relatively more active against severe bronchospasm than against milder stimuli. The antibronchoconstrictor effects on conscious guinea-pigs were blocked by propranolol but not by practolol even in much larger doses. Propranolol did not, however, block the effect on the isolated lung. It appears possible that the antibronchoconstrictor activity is a manifestation of the inhibition of phosphodiesterase.