Chronic hypoxic
pulmonary hypertension (
CHPH) is associated with altered expression and function of
cation channels in pulmonary arterial smooth muscle cells (PASMCs), but little is known for
anion channels. The Ca(2+)-activated Cl(-) channel (
CaCC), recently identified as TMEM16A, plays important roles in pulmonary vascular function. The present study sought to determine the effects of chronic
hypoxia (CH) on the expression and function of
CaCCs in PASMCs, and their contributions to the vascular hyperreactivity in
CHPH. Male Wistar rats were exposed to room air or 10% O(2) for 3–4 weeks to generate
CHPH.
CaCC current (I(CI.Ca)) elicited by
caffeine-induced Ca(2+) release or by depolarization at a constant high [Ca(2+)](i) (500 or 750 nm) was significantly larger in PASMCs of CH rats compared to controls. The enhanced I(CI.Ca)) density in CH PASMCs was unrelated to changes in amplitude of Ca(2+) release, Ca(2+)-dependent activation, voltage-dependent properties or
calcineurin-dependent modulation of
CaCCs, but was associated with increased TMEM16A
mRNA and
protein expression. Maximal contraction induced by
serotonin, an important mediator of
CHPH, was potentiated in endothelium-denuded pulmonary arteries of CH rats. The enhanced contractile response was prevented by the
CaCC blockers
niflumic acid and T16A(inh)-A01, or by the L-type Ca(2+) channel antagonist
nifedipine. The effects of
niflumic acid and
nifedipine were non-additive. Our results demonstrate for the first time that CH increases I(CI.Ca) density, which is attributable to an upregulation of TMEM16A expression in PASMCs. The augmented
CaCC activity in PASMCs may potentiate membrane depolarization and L-type channel activation in response to
vasoconstrictors and enhance pulmonary vasoreactivity in
CHPH.