The phosphodiesterase 5 (PDE5) inhibitor sildenafil citrate (Viagra; Pfizer) prevents and reverses cardiac hypertrophy (enlarging of the heart), according to a study in the February issue of Nature Medicine. Sildenafil, which failed to meet its endpoints in clinical trials for angina, is famous for its approval for treating erectile dysfunction (ED).
At least 11 PDE gene families are known to exist, many of which are promising targets for a range of diseases, including asthma and schizophrenia. PDE enzymes convert the intracellular second messengers cyclic AMP and cyclic GMP into the corresponding nucleotides AMP and GMP. Inhibition of PDE activity allows the cyclic nucleotide to remain active as a second messenger, which in the case of PDE5 inhibition leads to sustained dilation of the arteries.
In hearts exposed to sustained pressure, a number of signalling pathways are activated that contribute to hypertrophic remodelling and progressive cardiac dysfunction, and finally to heart failure. Evidence indicates that the catabolism of cGMP is involved in this process. First, PDE5 is expressed in the myocardium. Although expression levels are low, recent data support the idea that localization of PDE5 in cardiac muscle cells provides a means to potently regulate stress responses in the heart induced by adrenergic stimulation. In addition, hyperstimulation of cGMP synthesis using genetic engineering can blunt cardiac remodelling in animals exposed to pressure loading, although so far there has been little success with small-molecule approaches. Both synthetic and catabolic approaches trigger the heart's intrinsic signalling system, which is coupled to cGMP that can inhibit myocardial proliferative responses.
Now, David Kass and colleagues demonstrate an important role for PDE5 in cardiac hypertrophy. The authors subjected mice to chronic pressure overload by transverse aortic constriction. Blocking of PDE5 with sildenafil suppressed the myocyte hypertrophy, remodelling and fibrosis seen in control mice. Furthermore, sildenafil also reversed established hypertrophy and improved cardiac function, despite the sustained load. The authors found that PDE5 inhibition deactivates many of the signalling pathways associated with remodelling and hypertrophy in pressure-overloaded hearts, although not when particular pathways such as calcineurin or AKT were genetically overexpressed. The latter indicates that PDE5 inhibition affects more upstream targets.
In addition to treating ED, sildenafil is in trials for conditions such as pulmonary hypertension, leading to the possibility of its use as a chronic therapy. Success in these trials may facilitate clinical testing for hypertrophic heart disease. The recent study also demonstrated efficacy with another PDE5 inhibitor, tadalafil (Cialis; Lilly ICOS), which could indicate a drug-class effect.
References
ORIGINAL RESEARCH PAPER
Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nature Med. 21, 214–222 (2005)
FURTHER READING
Ashburn, T. T. & Thor, K. B. et al. Drug repositioning: identifying and developing new used for existing drugs. Nature Rev. Drug Discov. 3, 673–683 (2004)
Rotella, D. P. Phosphodiesterase inhibitors: current status and potential applications. Nature Rev. Drug Discov. 1, 674–682 (2002)
Takimoto, E. et al. cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ. Res. 96, 100–109 (2005)
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Brazil, M. Viagra for broken hearts?. Nat Rev Drug Discov 4, 190 (2005). https://doi.org/10.1038/nrd1670
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DOI: https://doi.org/10.1038/nrd1670