INTRATRACHEAL ADMINISTRATION OF PHOSPHODIESTERASE-III INHIBITOR ATTENUATES BRONCHOCONSTRICTION IN CATS - A PRELIMINARY-REPORT

The effects of intratracheal administration of MKS 492, a selective ph osphodiesterase (PDE) ill inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 mu g/kg), and the degree of b ronchoconstriction was assessed from increases in respiratory system r esistance (Rrs). All animals demonstrated good brofichoconstrictive re sponses (i.e., 86-99% increases in Rrs) to methacholine without tachyp hylaxis. On a separate day, the cats received the same four doses of m ethacholine after being pretreated with either intratrachael saline or three different doses of MKS 492 (0.17, 1.7, and 17 mu g/kg). The inc reases in Rrs with 1.7 mu g/kg [52.6 +/- 8.4% (SE)] and 17 mu g/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatm ent (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated ch anges in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced m ethacholine-induced bronchoconstriction in a dose-dependent fashion wi thout substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consid eration for clinical trials provided that more extensive preclinical i nvestigations justify such trials. Pediatr Pulmonol 1995; 19:360-364. (C) 1995 Wiley-Liss, Inc.