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PAH: treatment


A new class of treatment in PAH: sGC stimulators


In most PH patients, NO is depleted, so other enzymes that work independently of NO are of high medical need. Soluble guanylate cyclase is a critical component of the NO signalling pathway, and stimulators of this enzyme are a new class of treatment for PAH


Nika Skoro-Sajer MD Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria


The vascular pathology of PH results from pulmonary endothelial cell dysfunction accompanied by dysregulation of various signalling pathways,1


including


decreased production of nitric oxide (NO)2 and prostacyclin3 endothelin-1.4


and increased levels of PH is a devastating disease in


which increased pulmonary vascular resistance (PVR) causes right heart hypertrophy, eventually leading to right heart failure and death. Drugs targeting the NO, endothelin-1, and prostacyclin signalling pathways to promote vasodilatation (phosphodiesterase-5 (PDE-5) inhibitors, endothelin receptor antagonists (ERAs) and prostacyclin analogues, respectively) have been developed to treat pulmonary arterial hypertension (PAH).1


These treatments


improved quality of life, but outcomes remain poor, and there is still a need for more effective and durable treatment options. Furthermore, the majority of patients with PH (those with PH associated with lung diseases or left heart disease) still have no proved pharmacological treatments.


NO signalling pathway and guanylyl cyclases


Guanylyl cyclases are a family of enzymes that catalyse the conversion of guanosine- 5’-triphosphate (GTP) to the second messenger cyclic guanosine-3’5’- monophosphate (cGMP). Guanylyl cyclases have evolved to synthesise cGMP in response to diverse signals, such as NO,


Figure 1: Schematic presentation of sGC Catalytic regions are shown in orange and the conserved NH2-terminal domains of the soluble guanylate cyclase (sGC) α1 and β1 subunits are shown in green.


peptide ligands and fluxes in intracellular calcium.5


Soluble guanylate cyclase (sGC) is


a major enzyme, and a critical component of the NO signalling pathway, which is expressed in the cytoplasm of almost all mammalian cells. sGC mediates a wide range of important physiological functions, such as inhibition of platelet aggregation, relaxation of smooth muscle, vasodilatation, neuronal signal transduction and immunomodulation.5 Stimulation of guanylyl cyclases and the resultant accumulation of cGMP regulates complex signalling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases (PDEs) and cyclic nucleotide-gated ion channels.5


They also play a central role in


the regulation of diverse pathophysiological processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis and retinal phototransduction. sGC is a heterodimeric protein consisting of α- and β-subunits, and expression of both subunits is required for catalytic activity6,7


(Figure 1). Four isoforms of sGC subunits have been identified so far:


α1, α2, β1 and β2. NO is a free radical that activates sGC by binding directly to heme forming a bond with iron, with the half-life between four minutes and three hours at 20°C.6


NO responsiveness.6


Removal of heme results in a loss of Impairments of the


NO–sGC–cGMP signalling pathway have been implicated in the pathogenesis of cardiovascular disease, including coronary artery disease, peripheral vascular disease and PH.8–10


Treatment targeting NO signalling pathway


Treatments that elevate NO levels (inhaled NO and NO-donor drugs) are unsuitable as long-term therapies for PAH owing to their short-lived effects and the development of tolerance.11


The long-term use of inhaled


NO is hampered by technical problems of administration; life-threatening rebound PH could occur following interruption of NO inhalation. Furthermore, treatment with NO-releasing agents has failed to produce beneficial long-term effects as, in most cases, pulmonary vasodilatation was counterbalanced by significant peripheral reduction in vascular resistance and reflex tachycardia. The therapeutic strategy targeting NO signalling pathway includes the inhibition of PDE-5, which regulates the conversion of the second messenger cGMP to GMP. PDE5 inhibitors only work dependent on NO – if NO is depleted in PH patients, inhibitors might not work sufficiently. Sildenafil, tadalafil, and vardenafil are the substances in this group of agents, showing both acute and long- term beneficial effects in patients with PAH. However, the treatment with PDE-5 inhibitors is not always effective in PH patients and needs to be combined with other available treatments. An alternative


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