Targeting the NO/sGC/cGMP signaling pathway in health and disease

2017-02-03T04:01:36Z (GMT) by Ravi, Ravina Maru
The therapeutic utility of the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine 3’5’-monophosphate (cGMP) pathway is well-recognised, with NO donors used in the treatment of diseases such as heart failure, acute hypertensive crisis and pulmonary hypertension. However, traditional nitrovasodilator therapy is somewhat limited due to the development of tolerance following prolonged administration. Furthermore, in vascular disease states such as hypertension, the NO/sGC/cGMP pathway appears to be dysfunctional. Such dysfunction is thought to arise as a consequence of oxidative stress and the associated increase in vascular superoxide anion radical (•O2-) levels, leading to enhanced scavenging of NO to form the oxidant, peroxynitrite (ONOO-). Indeed, ONOO- is able to oxidise the reduced (Fe2+) heme group of sGC, converting it into its NO-insensitive ferric (Fe3+) or heme-free forms. Under such conditions, the efficacy of NO donors/nitrovasodilators are compromised, due to their inability to target these altered states of sGC, underlining the need for novel non-NO based compounds. As such, this thesis examines the vaso-protective actions and therapeutic potential of the redox sibling of NO, nitroxyl (HNO), as well as NO-independent sGC stimulators (BAY 41-2272) and activators (BAY 58-2667) in a number of cardiovascular disease states. From a clinical perspective, NO-independent compounds such as HNO donors and/or stimulators and activators of sGC may offer considerable therapeutic advantages over traditional nitrovasodilator therapies due to their well-documented resistance to •O2- scavenging and vascular tolerance development, as well as the ability to target oxidised/heme-free sGC (i.e. BAY 58-2667) and the potential to mediate their effects via cGMP-independent mechanisms of action. Such compounds may also offer the basis from which future therapies, for the treatment of cardiovascular diseases, are designed.