The NO - K+ channel axis in pulmonary arterial hypertension. Activation by experimental oral therapies.
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. Endothelial-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 vasodilatation and regression of PA remodeling. Several inexpensive oral treatments may be able to enhance the NO axis and/or K+ channel expression/function and selectively 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 BK(Ca). channels and relaxing PAs. In PAH, sildenafil (50 mg-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 decreases 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.
Michelakis
Evangelos D
ED
University of Alberta Hospitals, 2C2 Walker C McKenzie Health Sciences, Centre, Edmonton, Canada.
McMurtry
M Sean
MS
Sonnenberg
Brian
B
Archer
Stephen L
SL
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001120:Arginine / Q000008:administration & dosage; D003999:Dichloroacetic Acid / Q000008:administration & dosage; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000008:administration & dosage / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D015221:Potassium Channels / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011687:Purines; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D015221:Potassium Channels; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D001120:Arginine; D003999:Dichloroacetic Acid; D000068677:Sildenafil Citrate