Abstract
The soluble guanylate cyclase (sGC) stimulators riociguat and vericiguat elevate intracellular cyclic guanosine monophosphate (cGMP) levels via stimulation of the nitric oxide–sGC–cGMP pathway resulting in vasodilatory, anti-inflammatory, anti-proliferative, and anti-fibrotic effects
Highlights
Pulmonary hypertension (PH) is a broad term encompassing a variety of disorders, defined by a mean pulmonary artery pressure ≥25 mmHg1
PH is classified into five World Health Organization (WHO) groups[5]: Group 1: Pulmonary arterial hypertension (PAH), a category that contains several disorders/ subgroups, including idiopathic pulmonary arterial hypertension (PAH), heritable PAH, and PAH associated with certain conditions such as connective tissue diseases (e.g. diffuse cutaneous systemic sclerosis), congenital heart disease (CHD), and human immunodeficiency virus infection
Riociguat was the first drug to demonstrate efficacy and tolerability in two separate PH indications, namely PAH and inoperable or persistent/recurrent CTEPH17, . 18,23,24 This raised the possibility that soluble guanylate cyclase (sGC) stimulators may have efficacy in other forms of PH
Summary
Pulmonary hypertension (PH) is a broad term encompassing a variety of disorders, defined by a mean pulmonary artery pressure (mPAP) ≥25 mmHg1. SGC stimulators are a novel class of therapeutics with vasodilatory, anti-inflammatory, antiproliferative, and anti-fibrotic effects in various in vitro and in vivo models[9,10,11] These diverse actions mean that sGC stimulators have the potential to treat many other diseases, including heart failure (HF), systemic sclerosis, and cystic fibrosis. SGC stimulators have a dual mode of action; they enhance the sGC response to endogenous NO and directly stimulate sGC independent of NO via a different binding site, leading to elevation of cGMP (Figure 1)[8,12] This differs from phosphodiesterase type 5 (PDE5) inhibitors (another PAH-approved drug class), which prevent the breakdown of cGMP by occupying the catalytic site on PDE5.
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