Industry Insights

Phosphodiesterase inhibitors- not only a “little blue pill

It’s quite rare for an enzyme to catch so much of the public attention. Few would recognise the term “cyclic nucleotide phosphodiesterases (PDEs)”; however, few people would fail to recognise the word “Viagra” and its position as a blockbuster drug. PDEs are incredibly important enzymes and their role is increasingly being explored in areas other than sexual dysfunction, such as pulmonary hypertension and bronchodilatation. This article provides a brief overview of PDEs, the surrounding biochemistry and the growing body of knowledge being created through the use of fresh, functional human tissues.

PDEs selectively inactivate the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), by controlling their rates of degradation. PDE inhibitors prevent such inactivation and lead to a rise in cAMP or cGMP levels within the cell, thereby activating biochemical pathways (of which cAMP and cGMP influence many). PDEs represent an important enzyme class comprising 11 gene-related families of isozymes: PDE1 to PDE11. Most cells contain multiple PDEs that have overlapping specificities and affinities for cAMP or cGMP; however, it seems that while there may be some degree of redundancy in function, each of the PDEs provides significant regulatory control in a particular cell or region of a cell.


PDEs have long been pursued as pharmacological targets due to the multiplicity of their biochemical and structural properties, transcriptional and posttranscriptional regulation, specific subcellular compartments and their unique substrate binding requirements.

Selective PDE inhibitors are currently being studied in a wide array of diseases including the use of PDE2 inhibitors in sepsis; PDE5 inhibitors to treat cardiovascular disease and pulmonary hypertension; PDE4 inhibitors to treat asthma, COPD, allergic rhinitis, psoriasis, multiple sclerosis, depression, Alzheimer's disease and schizophrenia. As a result of its high expression in the vasculature, PDE3 was identified as a potential therapeutic target in cardiovascular disease and PDE3 inhibitors were initially investigated for the treatment of heart failure, but their use for this indication has fallen out of favour because of problematic arrhythmic side effects.

The feasibility of PDEs as drug targets is embodied by the clinical and commercial successes of the erectile dysfunction drugs: sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). Selective inhibitors for most PDE families largely remain commercially unavailable, despite the great need for their use in biochemical investigations and clinical settings. This drives much of the existing activity to identify novel PDE inhibitors and the recent emphasis on the use of human functional tissues to model PDE activity.

Through an extensive array of ex vivo human tissue assays, Biopta is able to provide early indications of drug safety, efficacy and absorption. Biopta’s areas of expertise include, for example, inflammation tissue culture models, vascular contractility and permeability studies, bi-directional membrane transport and ion channel studies. The standard tissue techniques utilized at Biopta include wire and perfusion myographs, organ baths, Ussing chambers and fresh organocultures.

The figures bellow illustrate some examples from Biopta’s assay catalogue which includes industry's widest range of human functional tissue assays.

Figure 1: Effects of sildenafil, a PDE5 inhibitor, on the constriction responses of (A) human resistance arteries from the skin (n = 3) and (B) human resistance chorionic plate arteries from the placenta (n = 6).  Sildenafil promotes degradation of cGMP, which regulates blood flow.



Figure 2: Effects of Milrinone, a PDE3 inhibitor, on the electrical field evoked constriction responses of human atrial trabeculae (n = 2).  Milrinone works to increase the heart's contractility and is a medication used in patients suffering from heart failure (although its use is less common now due to studies showing that it may increase mortality)..

In addition to the well characterised effects of PDE inhibitors in the cardiovascular system, PDEs are important in many other tissues, where again the use of human tissues and comparative studies between humans and animals are of high interest.

In the lung, PDEs 1 – 5 are expressed in human airway smooth muscle. Inhibitors directed at specific isoenzymes such as Rolipram (PDE4) and mixed or nonspecific inhibitors such as Zardavarine (PDE3/4) or Theophylline can be applied to human bronchi in the organ bath setting or in organoculture. In a similar way Biopta can produce data on the ability of clinically utilised and novel PDE antagonists to inhibit parameters such as bronchoconstriction and inflammatory cytokine production. PDE inhibitors may be modelled in isolation as potential monotherapies or in combination with other clinically relevant agents such as β2 agonists, muscarinic antagonists and corticosteroids.

Phosphodiesterases also play a key role in the genitourinary system. In addition to the well-recognized effects on erectile dysfunction, PDEs may be useful targets in the treatment of overactive bladder. 

The control of smooth muscle tone by PDEs, in particular through the nitric oxide –cGMP pathway human bladder may be important in the bladder (based on reports of improvements in overactive bladder from those taking PDE5 inhibitors), but as with many tissue types, a number of PDE isoenzymes are expressed in bladder, prostate and urethra (for an overview of PDE expression in a wide range of human tissues, see Lakics et al. (2010)). Ribeiro recently reported that the PDE4 inhibitor, rolipram, was more potent than PDE5 inhibitors in relaxing isolated strips of human and pig bladder set up in wire myographs. For other isoenzymes, a functional role is yet to be elucidated, for example, PDE9 expression has been localized to the urothelium (Nagasaki et al. 2012) but its function is unclear. In addition to effects on smooth muscle tone, the action of PDE inhibitors may also be related to anti-inflammatory properties. It is known the PDE5 inhibitors are useful in the treatment of benign prostatic hyperplasia; this might be due to the inhibition of intraprostatic inflammation (Vignozzi et al. 2013).

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6. Lakics, V. et al., Neuropharmacology. 2010 Nov;59(6):367-74. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues.

7. Ribeiro, AS et al. J Sex Med. 2014 Apr;11(4):930-41. Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck.

8. Nagasaki, S. et al. BJU Int. 2012 Mar;109(6):934-40. Phosphodiesterase type 9 (PDE9) in the human lower urinary tract: an immunohistochemical study.

9. Vignozzi, L. et al. Prostate. 2013 Sep;73(13):1391-402 PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

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