Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.

Abstract

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% 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.

• Authors: Evangelos D Michelakis, M Sean McMurtry, Xi-Chen Wu, Jason R B Dyck, Rohit Moudgil, Teresa A Hopkins, Gary D Lopaschuk, Lakshmi Puttagunta, Ross Waite, Stephen L Archer
• Journal: Circulation (Circulation) Vol. 105 Issue 2 Pg. 244-50 (Jan 15 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 11790708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Delayed Rectifier Potassium Channels
• Enzyme Inhibitors
• Kcnb1 protein, rat
• Potassium Channels
• Potassium Channels, Voltage-Gated
• Protein Kinase Inhibitors
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex
• Shab Potassium Channels
• Dichloroacetic Acid
• Protein Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• CHO Cells
• Cells, Cultured
• Chronic Disease
• Cricetinae
• Delayed Rectifier Potassium Channels
• Dichloroacetic Acid (pharmacology)
• Electric Conductivity
• Enzyme Inhibitors (pharmacology)
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (metabolism, pathology, physiopathology, prevention & control)
• Hypoxia (metabolism, physiopathology, prevention & control)
• Immunoblotting
• Male
• Muscle, Smooth, Vascular (drug effects, physiology)
• Potassium Channels (metabolism)
• Potassium Channels, Voltage-Gated (biosynthesis, metabolism, physiology)
• Protein Kinase Inhibitors
• Protein Kinases
• Protein Serine-Threonine Kinases
• Pulmonary Artery (drug effects, pathology)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Dehydrogenase Complex (metabolism)
• Rats
• Rats, Sprague-Dawley
• Shab Potassium Channels