Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS

Abstract

The discovery of NO as both an endogenous signalling molecule and as a mediator of the cardiovascular effects of organic nitrates was acknowledged in 1998 by the Nobel Prize in Physiology/Medicine. The characterization of its downstream signalling, mediated through stimulation of soluble GC (sGC) and cGMP generation, initiated significant translational interest, but until recently this was almost exclusively embodied by the use of PDE5 inhibitors in erectile dysfunction. Since then, research progress in two areas has contributed to an impressive expansion of the therapeutic targeting of the NO-sGC-cGMP axis: first, an increased understanding of the molecular events operating within this complex pathway and second, a better insight into its dys-regulation and uncoupling in human disease. Already-approved PDE5 inhibitors and novel, first-in-class molecules, which up-regulate the activity of sGC independently of NO and/or of the enzyme's haem prosthetic group, are undergoing clinical evaluation to treat pulmonary hypertension and myocardial failure. These molecules, as well as combinations or second-generation compounds, are also being assessed in additional experimental disease models and in patients in a wide spectrum of novel indications, such as endotoxic shock, diabetic cardiomyopathy and Becker's muscular dystrophy. There is well-founded optimism that the modulation of the NO-sGC-cGMP pathway will sustain the development of an increasing number of successful clinical candidates for years to come. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx

Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide

“…After purification sGC was converted to its ferric state by a reaction with ODQ; the single peak at 393nm confirmed the successful preparation of fully oxidized sGC. In agreement with the current literature [15, 41], the activity of sGC with ferric heme was unaffected by NO reflecting the low affinity of Fe +3 sGC for NO. At the same time, Fe +3 sGC responded well to BAY58-2667, an sGC activator that has a higher affinity to sGC with oxidized heme.…”

“…The pool of ferric or heme-free sGC is much more susceptible to degradation [12, 13]. About fifteen years ago, NO-independent sGC activators and stimulators were discovered [14, 15]; these agents enhance sGC activity in a heme-dependent or -independent manner. sGC activators are unique for their ability to increase the catalytic activity of heme-free/oxidized sGC.…”

Mechanisms underlying blood pressure reduction by dietary inorganic nitrate

“…The free radical nature of NO makes it highly reactive with other radicals and transition metals such as in haem proteins (Figure ). A fundamental NO signalling pathway is the binding to haem in soluble guanylyl cyclase (sGC), forming an iron‐nitrosyl complex which activates the enzyme, leading to generation of cGMP with multiple effects in various organ systems, including vasodilation, nerve signalling, mitochondrial biogenesis and angiogenesis . The high affinity of NO for transition metals also explains its reversible inhibition of cytochrome c oxidase, thereby regulating mitochondrial function .…”

Pharmacology of the ‘gasotransmitters’ NO, CO and H2S: translational opportunities

“…The NO field is more than 3 decades old, but readers can find in this issue reviews on novel aspects of NO/cGMP signaling and on the therapeutic usefulness of components of this pathway in cardiovascular diseases (Papapetropoulos et al ., 2015) with or without co‐morbidities, such as metabolic diseases (Pechánová et al ., ). Sexual dysfunction (Yetik‐Anacak et al ., ) and male infertility (Buzadzic et al ., ) are additional fields where modulation of NO signaling bears therapeutic potential.…”

“…The current issue also contains practical guides for scientists just entering into the interesting field of gasotransmitter research, including technical guidelines to measure NO in biological samples (Csonka et al ., ), basic guidelines for H 2 S pharmacology (Papapetropoulos et al ., 2015), and the chemical characteristics and biological behaviors of CO‐releasing molecules (Schatzschneider, ).…”