Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.
نویسندگان
چکیده
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.
منابع مشابه
Voltage-Gated Potassium Channels Pulmonary Hypertension in Rats: Role of Increased Expression and Activity of Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic
Teresa A. Hopkins, Gary D. Lopaschuk, Lakshmi Puttagunta, Ross Waite and Stephen L. Evangelos D. Michelakis, M. Sean McMurtry, Xi-Chen Wu, Jason R.B. Dyck, Rohit Moudgil, Voltage-Gated Potassium Channels Pulmonary Hypertension in Rats: Role of Increased Expression and Activity of Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Print ISSN: 0009-7322. Online ISSN: 15...
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ورودعنوان ژورنال:
- Circulation
دوره 105 2 شماره
صفحات -
تاریخ انتشار 2002