doi: 10.1161/hc0202.101974
(Circulation. 2002;105:244.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats
Role of Increased Expression and Activity of Voltage-Gated Potassium Channels
From the Department of Medicine (Cardiology) and Vascular Biology Group (E.D.M., M.S.M., X.-C.W., J.R.B.D., R.M., L.P., R.W., S.L.A.), and the Department of Pediatrics and Cardiovascular Research Group (J.R.B.D., T.A.H., G.D.L.), University of Alberta, Edmonton, Canada.
Correspondence to Evangelos D. Michelakis, MD, Assistant Professor, Cardiology, University of Alberta, 2C2.36 Walter Mackenzie Health Sciences Centre, Edmonton, AB, Canada T6G 2B7. E-mail emichela{at}cha.ab.ca
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.
Methods and 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% FiO2) 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 IK, eliminated the acute hypoxia–sensitive IK, and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 µmol/L) increased IK 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 IK 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.
Key Words: hypertension, pulmonary • kinases • dichloroacetate • metabolism • ion channels
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