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Targeting the NO-sGC-cGMP Pathway in Pulmonary Arterial Hypertension

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Diagnosis and Treatment of Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by an increase of more than 25 mmHg in pulmonary arterial blood pressure and a pulmonary capillary wedge pressure ≤15 mmHg. If left untreated, PAH is fatal, with only 34 % survival rate after 5 years (D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT et al. Ann Intern Med 115, 343–9, (1991)). Pathologically, PAH is characterized by changes in the pulmonary arterial vascular wall leading to occlusion, increased pressure, right ventricular heart failure, and death. Current therapies for PAH include increasing the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) axis, improving the prostacyclin pathway, or inhibiting the endothelin pathway. The NO-sGC-cGMP axis is a critical signaling cascade in PAH. Nitric oxide activates sGC, resulting in the synthesis of cGMP, a key mediator of pulmonary arterial vasodilatation that may also inhibit vascular smooth muscle proliferation and platelet aggregation. Dysregulation of the NO-sGC-cGMP axis results in pulmonary vascular inflammation, thrombosis, and constriction and ultimately leads to death from right heart failure. In this chapter, we will briefly discuss the role of the NO-sGC-cGMP pathway in PAH, potential and established treatment modalities to target this pathway, and their clinical applications.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Handayama 1-20-1, Higashi-ku, Hamamatsu, 431-3192, Japan

    Hiroshi Watanabe

  2. Department of Physiology and Pharmacology, Des Moines University College of Osteopathic Medicine, 3200 Grand Avenue, Des Moines, IA, 50312, USA

    Quang-Kim Tran

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  1. Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

    Yoshihiro Fukumoto

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Watanabe, H., Tran, QK. (2017). Targeting the NO-sGC-cGMP Pathway in Pulmonary Arterial Hypertension. In: Fukumoto, Y. (eds) Diagnosis and Treatment of Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-287-840-3_11

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