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The NO − K+ Channel Axis in Pulmonary Arterial Hypertension

Activation by experimental oral therapies

  • Conference paper
Hypoxia

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 543))

Abstract

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,

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  1. Evangelos D. Michelakis
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  2. M. Sean McMurtry
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  3. Brian Sonnenberg
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  4. Stephen L. Archer
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Editors and Affiliations

  1. Colorado Center for Altitude Medicine and Physiology, University of Colorado Health Sciences Center, Denver, Colorado, USA

    Robert C. Roach  & Peter H. Hackett (President) &  (President)

  2. University of California, San Diego, La Jolla, California, USA

    Peter D. Wagner

  3. International Society for Mountain Medicine, Ridgway, Colorado, USA

    Peter H. Hackett (President) (President)

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Michelakis, E.D., McMurtry, M.S., Sonnenberg, B., Archer, S.L. (2003). The NO − K+ Channel Axis in Pulmonary Arterial Hypertension. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 543. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8997-0_21

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