Current Modulation of Guanylate Cyclase Pathway Activity-Mechanism and Clinical Implications

Abstract

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

Keywords: chronic heart failure (CHF); guanylate cyclase (GC); pulmonary arterial hypertension (PAH).

Figure 1

X-ray structure of soluble guanylate cyclase (sGC). Domain organization of the human α1β1GC heterodimer (PDB ID: 6JT1, 3.9 Å) (a) [16], interaction side view between heme and histidine 105 (his 105) (b) and α1β1GC catalytic domains that resembles the Chinese yin-yang symbol with both subunits arranged in a head-to-tail conformation (PDB ID: 4NI2, 1.9 Å) (c) [17].

Figure 2

Schematic illustration of pharmacological intervention in guanylate cyclase/cyclic GMP pathway. Guanylate cyclase-coupled receptor, membrane-bound guanylyl cyclase (mGC); soluble guanylate cyclase (sGC); natriuretic peptides type A, B and C (ANP, BNP and CNP); neprilysin (NEP); gaseous mediators–nitric oxide (NO) and carbon monoxide (CO); cyclic guanosine monophosphate (cGMP); guanosine triphosphate (GTP); guanosine monophosphate (GMP); phosphodiesterase type x (PDEx).