Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.
BACKGROUND
Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K(+) channels (Kv) in pulmonary artery (PA) smooth muscle cells (SMCs) and a shift in cellular redox balance toward a reduced state. We hypothesized that dichloroacetate (DCA), a metabolic modulator that can shift redox balance toward an oxidized state and increase Kv current in myocardial cells, would reverse CH-PHT.


RESULTS
We studied 4 groups of rats: normoxic, normoxic+DCA (DCA 70 mg. kg(-1). d(-1) PO), chronically hypoxic (CH), and CH+DCA. CH and CH+DCA rats were kept in a hypoxic chamber (10% FiO(2)) for 2 to 3 weeks. DCA was given either at day 1 to prevent or at day 10 to reverse CH-PHT. We used micromanometer-tipped catheters and measured hemodynamics in closed-chest rats on days 14 to 18. CH+DCA rats had significantly reduced pulmonary vascular resistance, right ventricular hypertrophy, and PA remodeling compared with the CH rats. CH inhibited I(K), eliminated the acute hypoxia-sensitive I(K), and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 micromol/L) increased I(K) in CH-PASMCs. In a mammalian expression system, DCA activated Kv2.1 by a tyrosine kinase-dependent mechanism. When given long-term, DCA partially restored I(K) and Kv2.1 expression in PASMCs without altering right ventricular pyruvate dehydrogenase activity, suggesting that the beneficial effects of DCA occur by nonmetabolic mechanisms.


CONCLUSIONS
DCA both prevents and reverses CH-PHT by a mechanism involving restoration of expression and function of Kv channels. DCA has previously been used in humans and may potentially be a therapeutic agent for pulmonary hypertension.
Michelakis
Evangelos D
ED
Department of Medicine, University of Alberta, Edmonton, Canada. emichela@cha.ab.ca
McMurtry
M Sean
MS
Wu
Xi-Chen
XC
Dyck
Jason R B
JR
Moudgil
Rohit
R
Hopkins
Teresa A
TA
Lopaschuk
Gary D
GD
Puttagunta
Lakshmi
L
Waite
Ross
R
Archer
Stephen L
SL
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002908:Chronic Disease; D006224:Cricetinae; D051668:Delayed Rectifier Potassium Channels; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015151:Immunoblotting; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels
D051668:Delayed Rectifier Potassium Channels; D004791:Enzyme Inhibitors; C496991:Kcnb1 protein, rat; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D051669:Shab Potassium Channels; D003999:Dichloroacetic Acid; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases