Could a drug that has been used for decades to treat gout one day help manage urinary symptoms and erectile dysfunction? This question inspired a study conducted by scientists at the LUTED Lab (Lower Urinary Tract Disorders & Erectile Dysfunction Laboratory) in the Department of Pharmacology at the University of Campinas (UNICAMP).
The study showed that probenecid enhanced the relaxation of the prostate, urinary bladder, and corpus cavernosum in experiments using rat tissues, opening new perspectives for the drug repurposing of this well-established medication.
The findings were published in the European Journal of Pharmacology and suggest that probenecid can enhance the activity of key signaling pathways responsible for smooth muscle relaxation, a mechanism involved in both the control of lower urinary tract symptoms (LUTS) and penile erection.
Although these findings are currently limited to experimental studies and do not yet support clinical use in patients, they expand our understanding of new strategies to enhance the effectiveness of existing treatments.
To better understand the significance of this research and its next steps, Farmaco em Foco spoke with Professor Fabiola Zakia Mónica, head of the LUTED Lab, and the publication’s co-first authors, Dr. Guilherme Ruiz Leonardi and M.Sc. Mariana Burille Moretti.
What do the prostate, urinary bladder, and erectile dysfunction have in common?
At first glance, the prostate, urinary bladder, and penis appear to have entirely different functions. However, they are closely connected in several ways.
The prostate produces part of the seminal fluid, the urinary bladder stores urine, and the erectile tissue of the penis is responsible for penile erection. Despite their distinct physiological roles, all three rely on the coordinated function of smooth muscle, which must contract and relax at the appropriate times to perform their normal functions.
For example, the smooth muscle in the wall of the urinary bladder remains relaxed as the bladder fills with urine and contracts during urination. In the prostate, smooth muscle contraction helps release prostatic fluid during ejaculation, where it mixes with sperm to form semen. In the penis, relaxation of the smooth muscle within the corpus cavernosum allows blood to flow in and accumulate, resulting in penile erection.
As people age, this finely regulated balance can become disrupted. One of the most common conditions is benign prostatic hyperplasia (BPH), a non-cancerous enlargement of the prostate. As the gland enlarges, it can compress the urethra (the tube through which urine passes) making it more difficult to empty the bladder.
As a result, many men develop lower urinary tract symptoms (LUTS), including difficulty urinating, a weak urinary stream, increased urinary frequency, urgency, and the sensation of incomplete bladder emptying.
Beyond their impact on quality of life, these patients frequently experience erectile dysfunction (ED), characterized by difficulty achieving or maintaining an erection.
Research has shown that LUTS and erectile dysfunction share several underlying biological mechanisms, particularly those involved in the contraction and relaxation of smooth muscle.
It was this connection that prompted researchers at the LUTED Lab to investigate new therapeutic strategies for treating these conditions.
In fact, this is not the first time that Farmaco em Foco has featured research from the group. In a previous article, we explored how drug repurposing (the strategy of identifying new therapeutic applications for existing drugs) can accelerate drug development while reducing both research costs and development time.
In this article, we focus on the group’s latest findings and discuss how they may pave the way for future therapies. If you would like to learn more about drug repurposing and why it has become such an important area of biomedical research, we encourage you to read our previous article.
The Messengers of Smooth Muscle Relaxation
But what determines whether smooth muscle contracts or relaxes?
Cells rely on chemical signals to coordinate their activities. Among these signals are two molecules with unfamiliar names but crucial roles: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These molecules act as intracellular second messengers, triggering a cascade of signaling events that ultimately lead to smooth muscle relaxation.
Simply put, the greater the activity of these molecules inside the cell, the greater the tissue’s ability to relax. This is why many drugs used to treat lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) work by directly or indirectly increasing the activity of these molecules or the signaling pathways they activate.
A well-known example is sildenafil and tadalafil, two drugs widely used to treat erectile dysfunction. They inhibit an enzyme called phosphodiesterase type 5 (PDE5), which is responsible for breaking down cGMP. In the corpus cavernosum, cGMP promotes smooth muscle relaxation, allowing blood to fill the erectile tissue and produce an erection.
In other words, sildenafil and tadalafil prevent cGMP from being degraded, allowing it to remain in the corpus cavernosum for longer. As a result, erections occur more easily in response to sexual stimulation.
Given the central role of cAMP and cGMP in regulating the function of the urinary bladder, prostate, and penis, the researchers asked an intriguing question: Could the activity of these signaling molecules be enhanced using an existing drug? The search for this answer led them to investigate probenecid.
Could a Long-Established Drug Find a New Purpose?
When we think about developing a new treatment, we often imagine scientists creating an entirely new drug. However, a faster and often more cost-effective strategy is to identify new therapeutic uses for existing medications. This approach, known as drug repurposing, has already been discussed in a previous Farmaco em Foco article.
Probenecid has been used for decades to treat gout by lowering uric acid levels in the body. However, researchers have recently discovered that it also affects several other biological pathways whose functions are only now beginning to be understood.
Among these are membrane transporters that act as cellular “exit gates.” These transporters export cAMP and cGMP out of the cell, thereby reducing their intracellular activity.
Probenecid can inhibit these transporters, potentially reducing the efflux of cAMP and cGMP. As a result, these signaling molecules remain inside the cell for longer, allowing the smooth muscle relaxation signal to be sustained for an extended period.
It was precisely this hypothesis that the researchers set out to test: Could probenecid enhance the effects of drugs that promote smooth muscle relaxation in the prostate, urinary bladder, and corpus cavernosum through this mechanism?
If so, probenecid could prove to be a valuable adjunct in the treatment of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS). Rather than replacing existing therapies, it could be used alongside them to enhance their therapeutic effects.
In fact, this would not be the first time that probenecid has been repurposed beyond the treatment of gout. Today, it is also used as an adjunct to antibiotic therapy. Professor Fabiola explains: “Probenecid is used in combination with certain classes of antibiotics to reduce their clearance and increase their half-life.”
In other words, probenecid slows the elimination of antibiotics from the body, allowing them to remain in circulation for longer. This makes it possible to achieve therapeutic effects with lower antibiotic doses, potentially reducing side effects. This is yet another example of the many biological pathways through which probenecid acts, highlighting its potential to optimize a variety of existing therapies.
How Did the Researchers Test This Hypothesis?
To determine whether probenecid could indeed enhance smooth muscle relaxation, the researchers performed experiments using isolated prostate, urinary bladder, and corpus cavernosum tissues from rats.
They exposed these tissues to different compounds known to induce smooth muscle relaxation through distinct biological mechanisms. The goal was to determine whether probenecid could potentiate these relaxation responses.
One of the compounds tested was tadalafil, a well-established drug used to treat erectile dysfunction and also prescribed to relieve certain urinary symptoms associated with benign prostatic hyperplasia (BPH).
The researchers also tested several other molecules that, although not used clinically to treat LUTS or erectile dysfunction, are widely employed in laboratory research because they directly activate the major intracellular pathways responsible for smooth muscle relaxation.
Some of these compounds stimulate the production of cAMP, others increase cGMP levels, while others activate cell-surface receptors that ultimately trigger increases in both signaling molecules.
An analogy may help illustrate this concept. Imagine that smooth muscle relaxation is a destination that can be reached by several different roads. Some roads pass through cAMP, others through cGMP, while still others reach these signaling pathways indirectly.
By testing compounds that act through different mechanisms, the researchers could identify which pathways are enhanced by probenecid and, consequently, determine which “roads” this drug helps facilitate.
In addition to measuring smooth muscle relaxation, the team also quantified intracellular cAMP and cGMP levels, allowing them to determine whether the observed relaxation was associated with the accumulation of these signaling molecules.
What Did They Find?
The results supported the researchers’ hypothesis. Overall, probenecid enhanced the relaxing effects of several smooth muscle relaxants, although the magnitude of this effect varied depending on the tissue studied.
In the urinary bladder, probenecid enhanced the relaxation induced by compounds acting primarily through cAMP. The researchers also observed increased intracellular cAMP levels, supporting the hypothesis that probenecid limits its export from the cell and prolongs its activity.
However, probenecid did not enhance relaxation induced by compounds acting through cGMP, nor did it increase intracellular cGMP levels.
These findings suggest that, in the urinary bladder, probenecid selectively enhances cAMP-dependent relaxation pathways but not those mediated by cGMP.
In the prostate, probenecid also enhanced smooth muscle relaxation produced mainly by cAMP-related compounds. When combined with one of these agents (salbutamol) it also increased intracellular cAMP concentrations.
The findings were even more striking in the corpus cavernosum. Here, probenecid potentiated the relaxing effects of multiple agents acting through both cAMP- and cGMP-dependent pathways. Consistent with these functional results, intracellular levels of both signaling molecules increased in the presence of probenecid.
Taken together, these findings indicate that probenecid does not selectively enhance a single smooth muscle relaxation pathway. Instead, it appears to increase intracellular levels of cAMP and/or cGMP, with the predominant signaling pathway depending on the tissue being studied, whether the urinary bladder, prostate, or corpus cavernosum.
Why Is This Discovery Important?
The findings suggest that probenecid may function as an enhancer of signaling pathways that promote smooth muscle relaxation, indicating that it could also increase the effectiveness of drugs acting through these mechanisms.
Rather than replacing current therapies, probenecid could eventually be used in combination with existing treatments to improve their efficacy. Such an approach could be particularly beneficial for patients who simultaneously experience LUTS, benign prostatic hyperplasia, and erectile dysfunction.
Another important advantage is that probenecid has been used safely in clinical practice for decades to treat gout. Because its safety profile is already well established for this indication, repurposing it for other diseases could accelerate the development of new therapeutic options.
Nevertheless, these findings do not mean that probenecid is currently ready for clinical use in treating LUTS or erectile dysfunction.
It is important to emphasize that all experiments in this study were performed using isolated rat tissues rather than human patients. Although this type of research is essential for understanding drug mechanisms and generating new hypotheses, results obtained in laboratory models do not always translate directly to humans.
Dr. Guilherme highlights this limitation: “This is only the first step. Additional studies, including clinical studies in humans, will be necessary to confirm whether probenecid is truly effective for treating erectile dysfunction, including when used in combination with tadalafil, the drug most commonly prescribed for this condition.”
Before probenecid can be considered a therapeutic option for these disorders, further studies in animal models followed by carefully designed clinical trials in humans will be required.
Only these studies will determine whether this strategy is truly effective, establish the optimal dosage, identify which patients are most likely to benefit, and, above all, confirm its safety for this new indication.
Professor Fabiola also highlighted ongoing work using human tissues: “We are currently testing probenecid in human prostate, bladder, and corpus cavernosum tissues. We already have preliminary data from some samples, and probenecid appears to be even more potent in human tissue.”
M.Sc. Mariana described the next phase of her research: “We would like to investigate the effects of probenecid in pathological tissues. In my case, this includes benign prostatic hyperplasia using both animal and human models, as well as cell culture. These studies will help confirm the effectiveness of repurposing probenecid for this condition.”
Although considerable research remains before probenecid can be considered a new therapeutic option, these findings reinforce the value of drug repurposing as a strategy for accelerating the discovery of new treatments.
Professor Fabiola also emphasized the broader significance of the findings: “Urological disorders often coexist in men. A patient may have erectile dysfunction, overactive bladder, and benign prostatic hyperplasia simultaneously. By showing that probenecid enhances the relaxing effects of different mediators in all three organs, we now have a single compound capable of acting on three different tissues.”
The work conducted by the LUTED Lab advances our understanding of the biological mechanisms underlying lower urinary tract symptoms and erectile dysfunction, opening new avenues for the development of more effective therapies. As with all scientific research, each discovery lays another stone on the path toward future medical advances, bringing researchers closer to treatments that once seemed out of reach.
The research highlighted in this article was supported by the São Paulo Research Foundation (FAPESP; grant numbers 23/12406-3 and 24/03517-9).
This article was produced with the support of the São Paulo Research Foundation (FAPESP), Brazil (grant no. 25/17158-3). The opinions, hypotheses, conclusions, and recommendations expressed herein are those of the author(s) and do not necessarily reflect the views of FAPESP.
Further Reading
Original research article (DOI: 10.1016/j.ejphar.2026.179197)
Previous Farmaco em Foco article on LUTED Lab research
Written by:
Mia Schezaro Ramos
Pharmacist. Ph.D. in Pharmacology. Science journalist, illustrator, trans, Nintendo enthusiast, K-pop fan, and dependent on physical exercise to stay sane.