Pharmacological characterization of probenecid in isolated organs of the lower genitourinary tract and in models of erectile and micturition dysfunction: possible repositioning of probenecid?

Abstract

Introduction: Lower urinary tract symptoms (LUTS) encompass complications in storage (urgency, daytime frequency, nocturia, and urgency incontinence), voiding (slow stream, intermittency, straining, terminal dribble, and dysuria), and post-micturition (feeling of incomplete emptying and post-micturition dribble). In Europe and North America, the prevalence of LUTS is over 60% in individuals aged over 40 years, while in Brazil, these symptoms affect 75% of the population over 40 years old, with 69% in men and 82% in women. The impact of LUTS is broad and significant, leading to impairments in social, sexual, and financial quality of life. Preclinical and clinical trials have shown a strong correlation between LUTS and erectile dysfunction, estimating that approximately 70% of men with LUTS also have associated erectile dysfunction. Drug repurposing is a strategy that aims to redirect approved drugs for clinical use, studying new therapeutic indications. This strategy requires less time and funding, as much pharmacokinetic and toxicological information in animals and humans is already available. In this project, the focus is on probenecid, a uricosuric agent that may act as an inhibitor of multidrug resistance proteins (MRPs), activator of the transient receptor potential cation channel V2 (TRPV2), inhibitor of organic anion transporters (OATs), and panexin-1 channels that transport adenosine triphosphate (ATP). Objective: To perform a pharmacological characterization of probenecid in isolated lower genitourinary tract organs (bladder, prostate, and corpus cavernosum) from rodents and non-rodents, as well as human samples. Additionally, to evaluate the effect of probenecid on cell culture and isolated lower genitourinary tract organs in animal models of erectile and prostatic dysfunction. Preliminary Results: Probenecid produced a modest relaxation in the bladder and corpus cavernosum of rat, pig, or human, which was antagonized by some pharmacological tools, including those that interferes in the ATP pathway. Moreover, probenecid significantly potentiated relaxations induced by ligands that increase intracellular levels of cAMP and/or cGMP. Hypothesis/Justification: Based on this information, the hypothesis is that probenecid promotes relaxation of the smooth muscle of the bladder, corpus cavernosum, and prostate by activating the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway and/or adenylate cyclase-cyclic adenosine monophosphate (cAMP) pathway and/or reducing ATP release. Thus, probenecid may act as an agent that inhibits the mechanisms of erectile dysfunction and hypercontractility in benign prostatic hyperplasia and overactive bladder. Furthermore, probenecid may enhance the effects of clinically approved medications, such as tadalafil or mirabegron, on relaxing the prostate, bladder, and corpus cavernosum in animal models of erectile and prostatic dysfunction. (AU)