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1 Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine at Mount Sinai Medical Center, Miami Beach, Florida 33140; and 2 Inspire Pharmaceutical, Inc., Durham, North Carolina 27703
The purpose of
this study was to determine whether aerosolized INS316 (UTP) stimulates
lung mucociliary clearance (MCC) in sheep and, if so, to compare its
effects with INS365, a novel P2Y2-receptor agonist. In the
first series of studies, we used a previously described
roentgenographic technique to measure tracheal mucus velocity (TMV), an
index of MCC, before and for 4 h after aerosolization of INS316
(10
1 M and
102 M) and INS365
(101 M and
102 M), or normal saline in
a randomized crossover fashion (n = 6). In a second series of studies, we compared the ability of these agents to enhance total lung clearance. For these tests, the clearance of inhaled technetium-labeled human serum albumin was measured serially
over a 2-h period after aerosolization of
101 M concentration of each
agent (n = 7). Aerosolization of both P2Y2-receptor agonists induced
significant dose-related increases in TMV
(P < 0.05) compared with saline. The
greatest increase in TMV was observed between 15 and 30 min after drug
treatment. The highest dose
(101 M) of INS316 produced
a greater overall stimulation of TMV than did INS365
(101 M). Both compounds,
compared with saline, induced a significant increase in MCC
(P < 0.05) within 20 min of
treatment. This enhancement in MCC began to plateau at 60 min. Although
the response to INS316 started earlier, there was no significant
difference between the clearance curves for the two compounds. We
conclude that inhaled P2Y2-receptor agonists can
increase lung MCC in sheep and that for
P2Y2-receptor stimulation TMV
accurately reflects changes in whole lung MCC.
tracheal mucus velocity; total lung clearance; pharmacology; airway receptors
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