Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats.

Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased.

Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns.

The activity of voltage-gated K(+) (K(V)) channels plays an important role in regulating pulmonary artery smooth muscle cell (PASMC) contraction, proliferation, and apoptosis. The highly conserved NH(2)-terminal tetramerization domain (T1) of K(V) channels is important for proper channel assembly, association with regulatory K(V) beta-subunits, and localization of the channel to the plasma membrane. We recently reported two nonsynonymous mutations (G182R and E211D) in the KCNA5 gene of patients with idiopathic pulmonary arterial hypertension, which localize to the T1 domain of KCNA5.

Hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells.

Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes pulmonary vascular remodeling characterized by significant vascular medial hypertrophy. Electromechanical and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, while changes in cytosolic Ca2+ concentration ([Ca2+](cyt)) are an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells (PASMC). Hypoxia-induced increases in [Ca2+](cyt) are, in part, mediated by selective inhibition of voltage-gated K+ (Kv) channels in PASMC.

Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells.

Mice are useful animal models to study pathogenic mechanisms involved in pulmonary vascular disease. Altered expression and function of voltage-gated K(+) (K(V)) channels in pulmonary artery smooth muscle cells (PASMCs) have been implicated in the development of pulmonary arterial hypertension. K(V) currents (I(K(V))) in mouse PASMCs have not been comprehensively characterized.

Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension.

The pore-forming alpha-subunit, Kv1.5, forms functional voltage-gated K(+) (Kv) channels in human pulmonary artery smooth muscle cells (PASMC) and plays an important role in regulating membrane potential, vascular tone, and PASMC proliferation and apoptosis. Inhibited Kv channel expression and function have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH).

Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells.

Acute hypoxia causes pulmonary vasoconstriction in part by inhibiting voltage-gated K(+) (Kv) channel activity in pulmonary artery smooth muscle cells (PASMC). The hypoxia-mediated decrease in Kv currents [I(K(V))] is selective to PASMC; hypoxia has little effect on I(K(V)) in mesenteric artery smooth muscle cells (MASMC). Functional Kv channels are homo- and/or heterotetramers of pore-forming alpha-subunits and regulatory beta-subunits.