New targets for overactive bladder-ICI-RS 2109

Aim: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms. Methods: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB. Results: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide–dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1, TRPV4, TRPA1, and TRPM4) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+-activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway—the canonical fibrosis pathway. Conclusions: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor

How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023

Aim: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. Methods: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence—Research Society. Results: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. Conclusion: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified

Identification of interstitial cells of Cajal in corporal tissues of the guinea-pig penis

This study shows for the first time the presence of interstitial cells of Cajal (ICC) and their possible role in the initiation of spontaneous excitation in the corporal tissue of the guinea-pig penis. ICC, which were identified by their c-kit immunoreactivity, were abundantly distributed in the corporal smooth muscle meshwork. Spontaneous increases in the intracellular calcium concentration ([Ca(2+)](i); calcium transients) were visualized in preparations loaded with the fluorescent dye fura-2. Ca transients originated from the boundary of muscle bundles and then spread throughout the meshwork (Ca waves). Ca waves were strongly suppressed by either CPA (10 μM), ryanodine (50 μM) or 2-APB (10 μM), and their synchronicity was disrupted by 18β-GA (30 μM). These results suggest that ICC in the corporal tissue may have a role as pacemakers to drive the bulk of smooth muscles, and that intracellular Ca(2+) stores and gap junctions are critical for the generation of spontaneous excitation

Heterogeneous CPA sensitivity of spontaneous excitation in smooth muscle of the rabbit urethra

1. To investigate the role of intracellular Ca stores in generating spontaneous excitation of the urethra, the effects of cyclopiazonic acid (CPA) on spontaneous contractions, transient increases in intracellular calcium concentration ([Ca(2+)](i); Ca transients) and depolarizations were examined in smooth muscles of the rabbit urethra. 2. In about 90% of circular smooth muscle (CSM) preparations, CPA (10 μM) increased the amplitude of spontaneous contractions by about 180% and reduced their frequency to some 25% of control values (CPA-resistant), while it readily abolished the contractions in the remaining preparations. 3. In about 70% of CSM preparations, CPA prevented the generation of spontaneous depolarizations termed slow waves, but increased their amplitude and duration in the remainder. CPA also prevented the generation of spontaneous Ca transients in about 40% of CSM preparations, while increasing their amplitude and duration in the remaining preparations. In CPA-resistant preparations that had been exposed to nicardipine (1 μM), subsequent CPA invariably abolished residual spontaneous depolarizations or Ca transients. CPA abolished caffeine-induced Ca transients in Ca-free solutions, suggesting that it effectively depleted intracellular Ca stores. 4. Longitudinal smooth muscles generated spontaneous action potentials, which had a shape distinct from that of slow waves in CSM. Spontaneous action potentials were abolished by nicardipine but not CPA. 5. Transmural nerve stimulation increased the frequency of Ca transients to give a sustained rise in [Ca(2+)](i), but inhibited their generation after blocking α-adrenoceptors with phentolamine (1 μM). These nerve-evoked responses were preserved in preparations that had been exposed to CPA. Similarly, both in control and CPA-treated CSM preparations, spontaneous Ca transients were accelerated by noradrenaline (NAd, 1 μM) and were suppressed by 3-morpholino-sydnonimine (SIN-1, 10 μM), a nitric oxide (NO) donor. 6. In conclusion, CSM of the urethra generates spontaneous activity, which depends on Ca release from intracellular Ca stores. However, after blocking this primary pacemaking mechanism, L-type Ca channel-dependent action potentials may drive CSM. Irrespective of the origin of pacemaking, neurally-released NAd and NO are capable of modulating spontaneous excitation