Overactive bladder (OAB) affects approximately 12% of the population, with its prevalence increasing with age (1). OAB not only decreases patients’ quality of life, but also places substantial strain on healthcare services. Antimuscarinics serve as the first-line pharmaceutical approach for OAB management, yet up to 70% of older adult patients discontinue their regimens of prescribed medications within the first year (2). The rationale underlying this is not well understood, however, some evidence suggests a lack of expected benefits or an increase in adverse side effects. Darifenacin, a newer generation antimuscarinic, has been identified to have an insurmountable antagonist effect in the bladder (3). This is not the case with other medications in the same class, suggesting a potential alternative mechanism of action beyond its muscarinic receptor targeting. Any alternative action could account for the side effects specifically associated with darifenacin and its observed low rates of patient adherence. It is hypothesised that multiple receptor systems could be influenced by darifenacin. Thus, this scientific study aimed to explore the impact of darifenacin on contraction in detrusor smooth muscle tissue samples and urothelium with lamina propria (U&LP) in a pig animal model.

Porcine bladders from adult Large-White-Landrace pigs (Suf scrofa domestica, approximately 2-years-old, 200 kg live-weight) were obtained from a local abattoir after slaughter. Ethics was not required for offal use, as the animals were culled for the routine commercial provision of food. As such, no animals were bred, harmed, culled, interfered, or interacted with at all as part of this project. Porcine bladders were dissected into either detrusor or U&LP strips. Strips of porcine detrusor or porcine U&LP were mounted in carbogen-gassed Krebs-bicarbonate solution at 37°C. Single-dose response experiments were conducted, with the treatment of darifenacin (100nM) 30 mins before the application of one of seven agonists: serotonin (100µM), prostaglandin E2 (10µM), histamine (100µM), αβ-methylene-ATP (10µM), angiotensin II (100nM), neurokinin A (300nM), and carbachol (10µM).

Results indicated that darifenacin significantly decreased the maximum contraction response in detrusor preparations to carbachol by 43%, αβ-methylene ATP by 57%, prostaglandin E2 by 73%, histamine by 75%, and serotonin by 56%. In U&LP preparations, darifenacin reduced maximum contraction to carbachol by 49% and αβ-methylene ATP by 42%. All other agonists were not influenced by darifenacin.

It is a novel revelation that darifenacin has non-muscarinic mechanisms on purinergic, serotonin, histamine, and prostaglandin induced detrusor contractions. Given the present difficulties associated with patient adherence to antimuscarinic medications for managing OAB, these findings suggest that darifenacin modulates non-muscarinic pathways in adult urinary bladder tissue, potentially offering therapeutic benefits for OAB patients with a non-muscarinic pathophysiology.

Darifenacin has surfaced as an antimuscarinic with alternative targets in the bladder, with the ability to supress PGE2, αβm-ATP, 5HT, histamine and muscarinic induced contractions in the detrusor, and supress αβm-ATP and muscarinic induced contractions in the U&LP.

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Vouri SM, Schootman M, Strope SA, Xian H, Olsen MA. Antimuscarinic use and discontinuation in an older adult population. Arch Gerontol Geriatr. 2019; 80:1-11. doi: 10.1016/j.archger.2018.09.005
Veer V, Chess-Williams R, Moro C. Antimuscarinic actions on bladder urothelium and lamina propria contractions are similar to those observed in detrusor smooth muscle preparations. Neurourol Urodyn. 2023;42(5):1080-1087. doi: 10.1002/nau.25176.