5‐HT_2A receptor enhancement of contractile activity of the porcine urothelium and lamina propria

Abstract

Objectives:The urothelium and lamina propria play important roles in the maintenance of normal bladder function. Recently, contraction has been added to the properties the tissue possesses, but little is known about the mechanisms regulating this activity. This study examines the actions of 5-HT (serotonin) on the contractile properties of the urothelium and lamina propria, since a better understanding of bladder physiology may aid the development of new treatments. Methods: Strips of porcine urothelium and lamina propria were suspended in gassed Krebs-bicarbonate solution and cumulative concentration-response curves to 5-HT were generated in the absence and presence of 5-HT antagonists, L-NNA and indomethacin. Responses to α-methyl-5-hydroxytryptamine were also examined. Results: Strips of urothelium/lamina propria developed spontaneous contractions, while the addition of 5-HT induced concentration-dependent increases in contractile tone with maximal contractions of 50.43 ± 2.78mN per gram tissue weight (n=100). Tonic contractions to 5-HT were unchanged in the presence of L-NNA (100µM) or indomethacin (5µM). Selective concentrations of the antagonists methiothepin (5-HT1&2, 100nM), RS102221 (5-HT2C, 30nM), ondansetron (5-HT3, 30nM), GR113808, (5-HT4, 100nM), SB699551 (5-HT5, 10nM), SB399885 (5-HT6, 100nM), SB269970 (5-HT7, 10nM) did not influence responses to 5-HT. However, the 5-HT2A antagonist ketanserin (30-300µM) caused a shift of the 5-HT curve yielding an affinity estimate of 7.9. Conclusions:The results indicate that contractile responses of the urothelium/lamina propria to 5-HT are predominantly mediated via the 5-HT2A receptor.

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

“…Some of the chemicals that are capable of mediating contractions in the bladder include ATP 51 , 5-HT or serotonin 41 , prostaglandins 52 and histamine 11 . Specifically, histamine exerts its function in both U&LP and detrusor smooth muscle via the activation of the H1 receptor as confirmed in guinea pig [19][20][21] , rabbit 22 and pig 11 animal models.…”

“…It also enhances the mechanosensitivity of nearby afferent nerves to bladder distension, resulting in an increased neuronal activation in the spinal cord 40 . In addition, this effect may work in conjunction with other inflammatory-cell released chemicals such as 5-HT 41 to induce or maintain various lower urinary tract disorders. However, it is unclear how age affects the contractile responses to histamine.…”

Editorial Comment to 5‐HT2A receptor enhancement of contractile activity of the porcine urothelium and lamina propria

“…have clearly shown that the contractile responses of the urothelium/LP to 5-HT were predominantly mediated by a 5-HT 2A receptor, although the receptor subtype mediating muscle contraction on the porcine detrusor has yet to be established. 2 It has currently been reported that the contractile responses to 5-HT were significantly increased in bladder outlet obstruction rat detrusor strips, whereas the responses to KCl, carbachol or phenylephrine were not different compared with the controls. The 5-HT-induced contraction in bladder outlet obstruction rat detrusor strips was inhibited by a 5-HT 2A receptor antagonist.…”

“…In the present study, Moro et al . have clearly shown that the contractile responses of the urothelium/LP to 5‐HT were predominantly mediated by a 5‐HT 2A receptor, although the receptor subtype mediating muscle contraction on the porcine detrusor has yet to be established …”

The five primary prostaglandins stimulate contractions and phasic activity of the urinary bladder urothelium, lamina propria and detrusor

“…Furthermore, significantly increased expression of histamine receptors had been noted in patients with BPS/IC [13]. The actions of inflammatory mediators not only can cause urinary bladder contractions [14][15][16][17] but also are known to sensitise afferent nerve endings resulting in an increased spinal cord neuronal activation [18,19]. Therefore, inflammation and the actions of these pro-inflammatory mediators may contribute to the development of the urinary frequency and urgency symptoms observed in OAB, and pain in IC/BPS.…”