Physiological role of histamine H2 receptor on bladder sensory function in rats

Aizawa N1, Fujita T1

Research Type

Pure and Applied Science / Translational

Abstract Category

Pharmacology

Abstract 90
Physiology and Pharmacology
Scientific Podium Short Oral Session 12
Wednesday 27th September 2023
18:27 - 18:35
Room 104CD
Animal Study Basic Science Pharmacology
1. Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
Presenter
Links

Abstract

Hypothesis / aims of study
A recent study revealed that histamine modulates the contractile activity of urinary bladder via H1 and H2 receptors [1]. However, physiological role of H2 receptor (H2R) subtype is still not fully understood. To disclose the physiological role of histamine and H2R in the bladder, we investigated the expression of H2R in the bladder, and examined effects of histamine and cimetidine, an H2R antagonist, on bladder function including the in vivo primary bladder single-unit afferent activities (SAAs) in rats.
Study design, materials and methods
Female Sprague-Dawley rats were used (9-11 weeks old). 
The expression of H2R in the bladder was evaluated following immunohistochemical procedures. In the separate rats, effects of histamine and cimetidine on bladder function were investigated using SAAs and cystometry (CMG) measurements.
In the SAAs measurements under isoflurane anesthesia, the fine filaments were dissected from the left L6 dorsal roots and placed across a bipolar electrode for monitoring SAAs. Nerve fibers primarily originating from the bladder were identified by electrical stimulation of the left pelvic nerve and by bladder distension. Nerves with conduction velocities (CV) more than 2.5 m/s were designated as Aδ-fibers and those with CV less than 2.5 m/s as C-fibers. Saline instilled until the intravesical pressure reached 30 cmH2O. SAAs measurements were performed two protocols: first, to confirm the effect of histamine itself (10 – 1000 μM cumulative instillation); second, to confirm the effects of cimetidine (30 mg/kg, intravenously) and its relationship with histamine.
Continuous CMG measurements were performed with intravesical saline instillation under urethane anesthesia (1.2 g/kg, intraperitoneally). After baseline recording (> 1 h), vehicle or cimetidine (30 mg/kg, intravenously) administered. Then, histamine (100 μM) was continuously instilled into the bladder.
Results
H2Rs were strongly expressed in the urothelium layer rather than the smooth muscle layer.
SAAs of both Aδ- and C-fibers were dose-dependently increased during histamine instillation, which were significant at 100 and 1000 μM (figures 1AB). SAAs of C-fibers, not Aδ-fibers, were also increased by cimetidine administration (figures 1CD).
In results of the CMG, peak micturition pressure in vehicle group was significantly decreased during histamine instillation compared with that in cimetidine group (figure 2B). None of the other CMG parameters (basal pressure, threshold pressure, intercontraction interval and voided volume) showed significant differences between the vehicle and cimetidine groups (figures 2AB).
Interpretation of results
SAAs measurements suggested histamine (more than 100 μM) facilitates bladder sensory function, which was consistent with a previous mouse study [2]. Present study further revealed that H2R may contribute the bladder sensory function, especially via C-fiber. As harmonized with these results, H2R mainly expressed on the urothelium, which actively participates in sensory functions, expressing various receptors for neurotransmitters.
In contrast, CMG measurements showed that histamine itself decreased peak micturition pressure, which was counteracted by cimetidine, suggesting histamine decreased detrusor contractile activity via H2R. Although we cannot conclude this physiological mechanism, there were several possibilities e.g., different G protein-coupled receptors (H1R: Gq-coupled contraction, H2R: Gs-coupled relaxation), H2R antagonists as cholinesterase inhibitors [3], and experimental setup including anesthesia, etc.
Concluding message
The present study provides evidence that H2R has a physiological role of bladder sensory function via mechanosensitive C-fiber in rats.
Figure 1 Representative traces of SAAs measurements (A and C), and integrated activities of Aδ- and C-fibers between groups (B and D, mean ± SEM.). CM: cimetidine. *P<0.05, **P<0.01: from before value (repeated measures ANOVA followed by Dunnett’s-test)
Figure 2 Representative traces of CMG measurements (A), and parameters between groups (B, mean ± SEM.). #P<0.05: between groups (unpaired Student’s t-test)
References
  1. Stromberga Z. et al., Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors, Sci Rep 2019; 9: 3899
  2. Grundy L. et al., Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1, Am J Physiol Renal Physiol 2020; 318: F298-f314
  3. Satoh H. et al., Exacerbation of nonsteroidal anti-inflammatory drug-induced small intestinal lesions by antisecretory drugs in rats: the role of intestinal motility, J Pharmacol Exp Ther 2012; 343: 270-7
Disclosures
Funding NONE Clinical Trial No Subjects Animal Species Rat Ethics Committee Institutional Animal Care and Use Committee of Dokkyo Medical University
Citation

Continence 7S1 (2023) 100808
DOI: 10.1016/j.cont.2023.100808

01/11/2024 09:17:10