Modulating NO-GC Pathway in Pulmonary Arterial Hypertension

Abstract

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

Keywords: nitric oxide; pulmonary arterial hypertension; right ventricle; riociguat.

Figure 1

NO Synthesis. Metabolic pathway of NO synthesis from arginine by endothelial, neuronal, or inducible isoforms of the enzyme NO synthase with concomitant formation of citrulline.

Figure 2

NO effects on the healthy myocardium. NOS–NO signaling effects on cardiovascular function are mediated through direct phosphorylation of myosin-binding protein C (MYBPC) and troponin I (TnI), which are responsible for the reduction in myofilament Ca²⁺ sensitivity.

Figure 3

The NO pathway in cardiac myocytes. A schematic illustration of Ca²⁺ fluxes during excitation-contraction in ventricular cardiomyocytes. This diagram depicts the most representative protein complexes and intercellular organelles involved in the cardiac excitation-contraction coupling. Efficient systolic contraction and diastolic relaxation is reliant on efficient Ca²⁺ handling through several processes. Diffusion of Ca²⁺ into the cytosol through LTCC, L-type Ca²⁺ channel; Ca²⁺-induced-Ca²⁺-release from the ryanodine receptors (RyRs); Sequestration of Ca²⁺ back in to the sarcoplasmic reticulum via the important Ca²⁺ pump sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA); and Expulsion of Ca²⁺ from the cell via sodium-calcium exchanger pumps (NCX); PLB, phopholamban; Ca²⁺, calcium.

Figure 4

Mode of action of riociguat and PDE5i. Riociguat acts on the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), and stimulates the enzyme independently of NO. On the other side, PDE5i bind to the catalytic site of the PDE5 enzyme to act as a competitive inhibitor of cGMP, avoiding its conversion to GMP.