Role of guanylate cyclase modulators in decompensated heart failure.

In this review we investigate the role of particulate and soluble guanylate cyclase (pGC and sGC, respectively) pathways in heart failure, and several novel drugs that modify guanylate cyclase. Nesiritide and ularitide/urodilatin are natriuretic peptides with vasodilating, natriuretic and diuretic effects, acting on pGC, whilst cinaciguat (BAY 58-2667) is a novel sGC activator. Cinaciguat has a promising and novel mode of action because it can stimulate cyclic guanosine-3',5'-monophosphate synthesis by targeting sGC in its nitric oxide-insensitive, oxidised ferric (Fe(3+)) or haem-free state. Thus, cinaciguat may also be effective under oxidative stress conditions resulting in oxidised or haem-free sGC refractory to traditional organic nitrate therapies. Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function.