Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: a preliminary report.
The effects of intratracheal administration of MKS 492, a selective phosphodiesterase (PDE) III inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 micrograms/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86-99% increases in Rrs) to methacholine without tachyphylaxis. On a separate day, the cats received the same four doses of methacholine after being pretreated with either intratracheal saline or three different doses of MKS 492 (0.17, 1.7, and 17 micrograms/kg). The increases in Rrs with 1.7 micrograms/kg [52.6 +/- 8.4% (SE)] and 17 micrograms/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatment (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in a dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials.
Hu
H
H
National Children's Medical Research Center, Tokyo, Japan.
Takata
M
M
Kusakawa
I
I
Fujita
M
M
Miyasaka
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002415:Cats; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D008297:Male; D014132:Trachea
D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3