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Vol. 288, Issue 3, 1242-1250, March 1999
University Department of Pharmacology, University of Oxford,
Oxford, United Kingdom
We investigated the effects of the Cl
channel
blockers niflumic acid, 5-nitro-2-(3-phenylpropylamino)-benzoic acid
(NPPB) and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) on endothelin-1 (ET-1)-induced constriction of rat small pulmonary arteries (diameter 100-400 µm) in vitro, following endothelium removal. ET-1 (30 nM) induced a sustained constriction of rat pulmonary
arteries in physiological salt solution. Arteries preconstricted with
ET-1 were relaxed by niflumic acid (IC50: 35.8 µM) and
NPPB (IC50: 21.1 µM) in a reversible and
concentration-dependent manner. However, at concentrations known to
block Ca++-activated Cl channels, DIDS (
500
µM) had no effect on the ET-1-induced constriction. Similar results
were obtained when pulmonary arteries were preincubated with these
Cl channel blockers. When L-type
Ca++ channels were blocked by nifedipine (10 µM), the
ET-1-induced (30 nM) constriction was inhibited by only 5.8%. However,
niflumic acid (30 µM) and NPPB (30 µM) inhibited the ET-1-induced
constriction by ~53% and ~60%, respectively, both in the
continued presence of nifedipine and in Ca++-free
physiological salt solution. The Ca++ ionophore A23187 (10 µM) also evoked a sustained constriction of pulmonary arteries.
Surprisingly, the A23187-induced constriction was also inhibited in a
reversible and concentration-dependent manner by niflumic acid
(IC50: 18.0 µM) and NPPB (IC50: 8.8 µM), but not by DIDS (500 µM). Our data suggest that the primary
mechanism by which niflumic acid and NPPB inhibit pulmonary artery
constriction is independent of Cl channel blockade. One
possibility is that these compounds may block the
Ca++-dependent contractile processes.
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