No abstract

Background-Chronic hypoxic pulmonary hypertension (CH-PHT) is associated with suppressed expression and function of voltage-gated K ϩ 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, normoxicϩDCA (DCA 70 mg · kg Ϫ1 · d Ϫ1 PO), chronically hypoxic (CH), and CHϩDCA. CH and CHϩDCA 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. CHϩDCA 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 mol/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. (Circulation. 2002;105:244-250.)

The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O 2 -responsive K ؉ channels. K ؉ channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K ؉ channels are not themselves ''O 2 sensors'' but rather respond to the reduced redox state created by hypoxic inhibition of candidate O 2 sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O 2 . Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K ؉ channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K ؉ current but lack the specificity to identify the O 2 -sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O 2 -sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages > airways and veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O 2 species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K ؉ current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O 2 sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O 2 sensor in mice.The pulmonary circulation is a low-resistance vascular bed. Within seconds of onset of alveolar hypoxia (1, 2), the small, muscular pulmonary arteries (PAs) serving the hypoxic area constrict. This hypoxic pulmonary vasoconstriction (HPV) diverts blood flow to better-ventilated alveoli, thereby matching ventilation to perfusion and optimizing systemic PO 2 .