Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy

The prognosis for patients with pulmonary hypertension remains poor despite recent treatment advances, and there is a need for therapies with new modes of action. Nitric oxide (NO) is an endogenous vasodilator, the levels of which are regulated throughout the lung to ensure preferential perfusion of well-ventilated regions. Drugs that act in synergy with endogenous NO would therefore promote pulmonary vasodilation while maintaining optimal gas exchange. Riociguat is an oral stimulator of the NO receptor soluble guanylate cyclase. It synergises with NO and has demonstrated vasodilatory and antiremodelling properties in preclinical studies. Riociguat has been shown to have a favourable safety profile in healthy volunteers and in patients with pulmonary hypertension. Pharmacokinetic analyses have revealed substantial interindividual variation, suggesting that individual dose titration will be required. In a proof-of-concept study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, riociguat improved cardiopulmonary haemodynamics from baseline. It also caused systemic vasodilation, which was well tolerated but should be monitored in future studies. Dose titration of riociguat should promote pulmonary vasodilation while maintaining control of systemic effects, and has been investigated in a phase-II study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Preliminary results indicate that phase-III trials are warranted.