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

Andreas Papapetropoulos, Adrian J. Hobbs, Stavros Topouzis

Research output: Contribution to journalReview article

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1397-1414
Number of pages18
JournalBritish Journal of Pharmacology
Volume172
Issue number6
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Phosphodiesterase 5 Inhibitors
Diabetic Cardiomyopathies
Nobel Prize
Duchenne Muscular Dystrophy
Erectile Dysfunction
Septic Shock
Heme
Pulmonary Hypertension
Nitrates
Theoretical Models
Up-Regulation
Heart Failure
Medicine
Enzymes
Research
Therapeutics
Optimism

ASJC Scopus subject areas

  • Pharmacology

Cite this

Extending the translational potential of targeting NO/cGMP-regulated pathways in the CVS. / Papapetropoulos, Andreas; Hobbs, Adrian J.; Topouzis, Stavros.

In: British Journal of Pharmacology, Vol. 172, No. 6, 01.01.2015, p. 1397-1414.

Research output: Contribution to journalReview article

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