Endothelin‐A‐receptor antagonist LU 302146 inhibits electrostimulation‐induced bladder contractions in vivo

Scheepe, Jeroen R.; Hoek, Joop van den; Jünemann, Klaus-Peter; Alken, P.

doi:10.1002/nau.20257

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…As mentioned above, ET-1 can bind to specific receptors to exert multiple effects on bladder functions such as inducing detrusor overactivity and modulating sensory function in the peripheral nervous system. 25 , 27 , 48 , 49 This study also revealed the key role of endothelin pathway in the induction of bladder hypersensitization and hyperalgesia. In comparison with saline infusion, ET-1 infusion further significantly decreased the pressure to trigger PT and VMR, together with a more forceful and longer VMR.…”

Section: Discussionsupporting

confidence: 52%

The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents

Qin¹,

Wang²,

Li³

et al. 2022

JIR

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Introductions Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood chronic disorder characterized by bladder-related pain. Chronic psychological stress plays a key role in the exacerbation and development of IC/BPS via unclear mechanisms. This study aimed to investigate the role of endothelin 1 (ET-1) and its receptors in the development of chronic stress-induced bladder dysfunction. Methods Wistar‐Kyoto rats were exposed to chronic (10 days) water avoidance stress (WAS) or sham stress, with subgroups receiving capsaicin pretreatment to desensitize C-fiber afferents. Thereafter, cystometrograms (CMG) were obtained with visceromotor response (VMR) simultaneously during intravesical saline or ET-1 infusion. CMG recordings were analyzed for the first and the continuous voiding cycles, respectively. Endothelin receptor type A (ETAR) expression was examined in the bladder tissues and L6-S1 dorsal root ganglions (DRGs). Toluidine blue staining was to check the bladder inflammation and double-labeling immunofluorescence (IF) staining was to identify the locations of ETAR, respectively. Results During saline infusion, WAS rats elicited significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/maximum intravesical pressure (IVPmax), and a significant increase in VMR duration and area under the curve (AUC). ET-1 infusion induced similar alternations in WAS rats, but further significantly diminished the pressure to trigger PT and VMR, together with a more forceful and longer VMR. The sole effect of WAS exposure or ET-1 administration on the micturition reflex could be suppressed by capsaicin pretreatment. WAS exposure significantly induced an increased number of total mast cells in the bladder, while capsaicin pretreatment possibly antagonized them. No significant difference in ETAR expression was found between all groups. IF staining indicated the co-localization of ETAR and calcitonin gene-related peptides in both bladder and DRGs. Conclusion The activation of ET-1 receptors could enhance chronic stress-induced bladder hypersensitization and hyperalgesia through capsaicin-sensitive C-fiber afferents. Targeting the endothelin pathway may have therapeutic value for IC/BPS.

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Section: Discussionsupporting

confidence: 52%

The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents

Qin¹,

Wang²,

Li³

et al. 2022

JIR

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“…This stimulation-induced rise in bladder pressure can be urodynamically evaluated and objectively quantified. Standardized stimulation parameters result in reproducible, stimulation-induced bladder contractions suitable for pharmacological evaluation of drug effects on bladder contraction [12] . In this study, the sacral root S2 was stimulated to evoke neurogenic-induced bladder contractions.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

Scheepe¹,

Braun²,

Jünemann³

et al. 2008

Urol Int

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Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects. Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively. Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure. Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

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“…ET-1 is able to decrease the micturition volume, an effect that could be blocked by ET-receptor antagonists [47]. The selective ET-A-antagonist, LU 302146, reduced the stimulation-induced pig bladder contraction in an atropine-inhibited way [48]. Experiments with i.v.…”

Section: Neuropeptidergic Systemmentioning

confidence: 99%

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

2008

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Antimuscarinics are the mainstay of the medical therapy for overactive bladder, but their side effects and often modest success have prompted studies on novel pharmacological approaches. In this paper, we give a systematic literature review of peer-reviewed papers on the subject. Effective nonantimuscarinic treatments are currently scarce, but many new promising compounds are emerging, which target key molecular pathways involved in micturition control. The most promising potential therapeutic targets include: nervous GABAergic, glycinergic, dopaminergic, and serotonergic systems; b-adrenoceptors and cAMP metabolism; nonadrenergic-noncholinergic mechanisms such as purinergic and neuropeptidergic systems; vanilloid receptors; bladder afferent nerves; nonneuronal bladder signaling systems including urothelium and interstitial cells; prostanoids; Rho-kinase; and different subtypes of potassium and calcium channels. Despite the enormous amount of new biologic insight, very few drugs with mechanism of action other than antimuscarinics have passed as yet the proof-of-concept stage. Further preclinical and clinical studies are urgently needed in this rapidly moving field.

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Endothelin‐A‐receptor antagonist LU 302146 inhibits electrostimulation‐induced bladder contractions in vivo

Cited by 6 publications

References 26 publications

The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents

The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

Emerging pharmacological targets in overactive bladder therapy: experimental and clinical evidences

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