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

Article

关键词: SMOOTH-MUSCLE CELLS;    CONGESTIVE-HEART-FAILURE;    MOLECULAR-IDENTIFICATION;    ARTERY MYOCYTES;    K+ CHANNELS;    TISSUE;   

DOI  :  10.1161/hc0202.101974

来源: SCIE

【 摘 要 】

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 IK, and decreased Kv2.1 channel expression. In the short term, low-dose DCA (1 mumol/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.

【 授权许可】

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