Advances in Cardiovascular Pharmacotherapy: VII. Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension and...

The nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway is a major regulator of cardiovascular and renal homeostasis that causes vasodilation and protects against maladaptive remodeling. Abnormal NO-sGC-cGMP signaling, characterized by decreases in NO synthesis, sGC activation, and cGMP formation, has been shown to play an essential role in the pathogenesis of 2 major phenotypes of pulmonary hypertension and in the development of heart failure. A new class of medications, known as sGC stimulators, circumvents the reduction in NO availability by binding directly to sGC and catalyzing the formation of cGMP independent of NO. The sGC stimulators also synergistically enhance the enzyme's activity when NO is bound. These actions increase cGMP production in vascular smooth muscle and myocardium, restoring the endogenous protective effects of the cascade. This article first briefly reviews the normal physiology of NO-sGC-cGMP signaling and discusses its pathophysiological implications. It then describes the development and biochemistry of sGC stimulators, including riociguat and vericiguat, their mechanism of action, and the pharmacologic rationale for their use in pulmonary hypertension and heart failure. It subsequently examines the clinical evidence supporting the use of these drugs in patients with chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and heart failure with reduced ejection fraction. Finally, the article comments on their potential anesthetic implications.