Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors

Abstract

The mechanisms underlying bladder contractile disorders such as overactive bladder are not fully understood, and there is limited understanding of the receptor systems modulating spontaneous bladder contractions. We investigated the potential for histamine to have a role in mediating contractility of the urothelium with lamina propria (U&LP) or detrusor via the H1-H4 histamine receptor subtypes. Isolated strips of porcine U&LP or detrusor smooth muscle were mounted in gassed Krebs-bicarbonate solution and responses to histamine obtained in the absence and presence of selective receptor antagonists. The presence of histamine increases the frequency of U&LP spontaneous phasic contractions and baseline tensions. In response to histamine, H1-antagonists pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting contractile responses. Cimetidine (H2-antagonist) enhanced increases in baseline tension in response histamine, whereas amthamine (H2-agonist) induced relaxation. Although thioperamide (H3/H4-antagonist) increased baseline tension responses to histamine, selective H1/H2-receptor antagonism revealed no influence of these receptors. In detrusor preparations, pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting baseline tension increases in response to histamine. Our findings provide evidence that histamine produces contractile responses both in the U&LP and detrusor via the H1-receptor, and this response is significantly inhibited by activation of the H2-receptor in the U&LP but not the detrusor.

Alterations in histamine responses between juvenile and adult urinary bladder urothelium, lamina propria and detrusor tissues

“…Intact strips of the urinary bladder were horizontally removed from the anterior base wall of the bladder dome region. Urothelium with lamina propria was dissected from the underlying detrusor layer, consistent with methods carried out in past studies 11,42 . Throughout the preparation and dissection stage, tissue strips were constantly washed with a cold Krebs-bicarbonate solution.…”

“…Histamine dihydrochloride, amthamine dihydrobromide, pyrilamine maleate salt, cimetidine, thioperamide maleate salt, indomethacin, atropine, and Nω-Nitro-L-arginine were obtained from Sigma-Aldrich (Missouri, USA), and fexofenadine hydrochloride, αβ-methylene ATP (sodium salt) and cyproheptadine hydrochloride hydrate from Cayman Chemicals (Michigan, USA). Concentrations chosen for the agonists and antagonists were selected based on their selectivity at each receptor and consistent with concentrations used in previous studies 11 .…”

“…One such system is the histaminic receptor system that is involved in the modulation of the urinary bladder contractions and spontaneous activity; 11 however it remains unclear how ageing impacts this receptor system. Histamine exerts its function by binding to four different G protein-coupled receptors: H1, H2, H3 and H4 12 .…”

“…However, it is unknown whether the histamine receptor system directly mediates contractions of the bladder dome and is associated with bladder pathologies. Histamine is known to induce significant increases in both the tension and frequency of spontaneous phasic contractions in both the urothelium with lamina propria and in the underlying detrusor muscle via the activation of the H1 receptors 11 . It also enhances the mechanosensitivity of nearby afferent nerves to bladder distension, resulting in an increased neuronal activation in the spinal cord 40 .…”

“…Based on prior histamine receptor expression research, it is hypothesised that responses from stimulating the H1 receptor will be reduced with ageing in both U&LP and detrusor smooth muscle. It is also hypothesised that stimulation of the H2 receptor, shown to be involved in inhibitory responses in urothelium with lamina propria 11 , will have a more significant impact on juvenile tissues when compared to adult tissues. The aim of this study was to compare responses to histamine in both U&LP and detrusor tissues from porcine juvenile and adult bladders.…”