Abstract
This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.
Highlights
Despite significant advances in the modern diagnosis and pharmacologic and nonpharmacologic therapy for heart failure, with a reduction of mortality of more than 50%, long-term prognosis of the disease still is poor and, often, with uncertain outcome [1, 2].The great expectations set in vasopeptidase inhibitors, tumor necrosis factor–ǂ antagonists, metalloproteinase inhibitors, endothelin antagonists, and adenosine A1-receptor antagonists could not be verified by findings as has been shown in large-scale clinical trials
Drugs that modulate soluble guanylate cyclase and cyclic guanosine 3’, 5’monophosphate levels are emerging as promising therapies for heart failure
NO—nitric oxide; NP—natriuretic peptide; RTK; particulate guanylate cyclase (pGC)—particulate guanylate cylase; sGC—soluble guanylate cyclase; cGMP—cyclic guanosine 3’, 5’-monophosphate; PDEs—phosphodiesterases; cGKs— cGMP-dependent protein kinases; GTP—guanosine-5'-triphosphate; PAK; GDP; IRAG—inositol 1,4,5trisphosphate receptor I–associated protein; cAMP—cyclic adenosine monophosphate. Both the NO–sGC–cGMP pathway and the NP–pGC–cGMP pathway are disordered in a range of cardiovascular conditions, including acute decompensated heart failure (ADHF) [10]
Summary
Despite significant advances in the modern diagnosis and pharmacologic and nonpharmacologic therapy for heart failure, with a reduction of mortality of more than 50%, long-term prognosis of the disease still is poor and, often, with uncertain outcome [1, 2]. Drugs that modulate soluble guanylate cyclase (sGC) and cyclic guanosine 3’, 5’monophosphate (cGMP) levels are emerging as promising therapies for heart failure. The sGC activator cinaciguat and sGC stimulators riociguat and BAY 60-4552 as modulators of sGC are promising drugs with favorable effects such as vasodilatation; inodilation; and antiproliferative, antiapoptotic, and antiremodeling effects through protein kinase G-type and phosphodiesterases as well as calcium ion channels [3]. Cinaciguat (BAY 58-2667) is a novel molecule that activates regulatory sites on both the ǂ and ǃ subunits of sGC, a key signal transduction enzyme that synthesizes cGMP in response to binding of nitric oxide. Riociguat revealed beneficial effects and good tolerability in patients with pulmonary hypertension [6] and patients with severe heart failure [7]. This article summarizes the pathophysiologic relevance and therapeutic potential of the sGC–cGMP signalling system in acute and chronic heart failure
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