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Turning on cGMP-dependent pathways to treat cardiac dysfunctions: boom, bust, and beyond

Robert Lukowski1, Thomas Krieg2, Sergei D Rybalkin3

  • 1Pharmacology, Toxicology, and Clinical Pharmacy, Institute of Pharmacy, Universität Tübingen, Tübingen, Germany.

Trends in Pharmacological Sciences
|June 21, 2014
PubMed

Insights

Targeting the cyclic guanosine monophosphate (cGMP) pathway for heart dysfunction shows mixed results. While preclinical studies suggest benefits, clinical trials for guanylyl cyclase modulators and PDE5 inhibitors like sildenafil have been inconclusive, questioning current strategies.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Pharmacology

Background:

  • Cyclic guanosine monophosphate (cGMP) plays a role in inhibiting cardiac hypertrophy, reducing fibrosis, and protecting against ischemia-reperfusion (I/R) injury.
  • While cGMP signaling is implicated in cardiac fibrosis and I/R injury, the specific role of its effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy remains unclear.

Purpose of the Study:

  • To review concerns regarding the efficacy of targeting the cGMP pathway for managing heart dysfunction.
  • To evaluate the clinical and preclinical evidence for agents that modulate cGMP levels.

Main Methods:

  • Review of preclinical and clinical studies on cGMP-modulating agents, including guanylyl cyclase (GC) modulators and phosphodiesterase 5 (PDE5) inhibitors.
  • Analysis of mechanistic considerations, including cellular localization of drug targets and potential off-target effects.

Main Results:

  • Clinical trial results for GC modulators are inconclusive.
  • Sildenafil (a PDE5 inhibitor) showed cardioprotection in mouse models but not in clinical trials.
  • Preclinical cardioprotection by sildenafil may be due to non-cardiomyocyte PDE5 inhibition or off-target effects (e.g., PDE1C).

Conclusions:

  • Current strategies targeting the cGMP pathway for heart dysfunction require re-evaluation.
  • Further investigation into the cellular localization of drug targets and optimized intervention protocols for cGMP-elevating agents is needed.

Keywords:
cGMP-dependent protein kinase type Icardiomyopathyguanylyl cyclasesnitric oxidephosphodiesterase 5protein kinase G

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