| Popis: |
The prognosis of patients with pulmonary arterial hypertension (PAH) is poor. Available therapies (Ca++ -channel blockers, epoprostenol, bosentan) have limited efficacy or are expensive and associated with significant complications. PAH is characterized by vasoconstriction, thrombosis in-situ and vascular remodeling. En-dothelial-derived nitric oxide (NO) activity is decreased, promoting vasoconstriction and thrombosis. Voltage-gated K+ channels (Kv) are downregulated, causing depolarization, Ca++ -overload and PA smooth muscle cell (PASMC) contraction and proliferation. Augmenting the NO and Kv pathways should cause pulmonary vaso-dilatation and regression of PA remodeling. Several inexpensive oral treatments may be able to enhance the NO axis and/or K+ channel expression/functioi and selective- ly decrease pulmonary vascular resistance (PVR). Oral L-Arginine, NOS’ substrate, improves NO synthesis and functional capacity in humans with PAH. Most of NO’s effects are mediated by cyclic guanosine-monophosphate (c-GMP). cGMP causes vasodilatation by activating K+ channels and lowering cytosolic Ca++ . Sildenafil elevates c-GMP levels by inhibiting type-5 phosphodiesterase, thereby opening BKCachannels and relaxing PAs. In PAH, sildenafil (50mg-po) is as effective and selective a pulmonary vasodilator as inhaled NO. These benefits persist after months of therapy leading to improved functional capacity. 3) Oral Dichloroacetate (DCA), a metabolic modulator, increases expression/function of Kv2. 1 channels and de creases remodeling and PVR in rats with chronic-hypoxic pulmonary hypertension, partially via a tyrosine-kinase-dependent mechanism. These drugs appear safe in humans and may be useful PAH therapies, alone or in combination |
