Bronchial vs. cardiovascular activities of selective phosphodiesterase inhibitors in the anesthetized beta-blocked dog.
This study was undertaken to determine whether isozyme-specific inhibitors of cAMP-selective phosphodiesterases (PDEs) induce bronchodilation without the cardiovascular side effects known to be produced by nonselective PDE inhibitors. The abilities of PDE inhibitors to reverse the bronchoconstriction induced by serotonin in a beta-blocked anesthetized dog were compared simultaneously with their effects on cardiac contractile force (+dP/dt), heart rate and blood pressure. Aminophylline and enprofylline, two antiasthma drugs with nonselective PDE inhibitory activity, produced dose-dependent (ED50S = 2.3 and 0.58 mg/kg, respectively) and complete (95-100%) bronchodilation accompanied by profound increases in cardiac force, tachycardia and decreases in blood pressure. Similar effects were observed with forskolin, a potent adenylate cyclase activator. Imazodan and CI-930 (inhibitors of the cGMP-inhibitable cAMP-selective PDE isozyme designated PDE-III) induced pulmonary and cardiovascular effects virtually identical to the nonselective PDE inhibitors, but with greater potency (ED50S = 0.02 and 0.04 mg/kg). In contrast, rolipram and Ro 20-1724 (inhibitors of a cGMP-insensitive cAMP-selective PDE isoform commonly designated PDE-IV) induced bronchodilation in the dog (ED50S = 0.007 and 0.63 mg/kg, respectively) without causing significant changes in cardiac force or heart rate, even after predosing dogs with forskolin. However, rolipram and Ro 20-1724 were less efficacious than the other inhibitors in that they induced only partial (50-60%) bronchodilation. The results suggest that canine respiratory muscle tension is regulated by both PDE-III and PDE-IV. Inhibitors of PDE-IV produce bronchodilation in the described model with minimal concomitant cardiac side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Heaslip
R J
RJ
Division of Immunopharmacology, Wyeth-Ayerst Research, Princeton, New Jersey.
Buckley
S K
SK
Sickels
B D
BD
Grimes
D
D
D000758:Anesthesia; D000818:Animals; D001980:Bronchi / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007527:Isoenzymes / Q000494:pharmacology*; D008297:Male; D010424:Pentobarbital; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D012702:Serotonin Antagonists; D010424:Pentobarbital