Novel targets for the pharmaceutical management of bladder contractile disorders: Identifying mediators of contraction in the urinary bladder urothelium

Bladder contractile disorders, such as overactive and underactive bladder, are highly prevalent and an increasing issue with age. However, current therapeutics used in its management are limited in their effectiveness, highlighting the importance of identifying novel targets for future treatments. One first step of this process is identifying the receptors present on the cells within the urothelium and lamina propria (U&LP) and investigating their role in mediating contractile activity (1, 2). It is also unknown whether the second-messenger actions of these various receptors hold similarities between them, or if there are unique stimulants of contraction which can be targeted in future therapeutics. This study aimed to identify the role of selected receptors for mediating bladder contractions and whether similar mechanisms remain consistent across a range of different surface receptors in the urothelium with lamina propria (U&LP). Porcine U&LP strips were isolated from the urinary bladder and mounted in organ baths containing Krebs-bicarbonate solution and perfused with carbogen gas at 37°C. Tissue baseline tension and frequency was recorded before and after the addition of a single dose of receptor agonist with concentrations chosen as per prior studies. After activation of the muscarinic (1µM), histamine (100µM), 5-HT (100µM), neurokinin-A (300nM), prostaglandin E2 (10 µM), and angiotensin II (100nM) receptors, the baseline tension of the U&LP tissue increased significantly (paired Student’s two-tailed t-test). Change in frequency significantly increased when activating the muscarinic, histamine and 5-HT receptors. The U&LP tissue layers of the urinary bladder contracted in response to each of the agonists, and increases in spontaneous contractile frequency demonstrate potential mediators for diseases such as overactive bladder. A greater understanding into the various mediators of contraction may help identify future therapeutic targets to be employed in the pharmaceutical management of bladder contractile disorders and provide further insights into the methods of contraction within the urinary bladder wall.