The enhancing effect of 5-HT on phasic contractions of human isolated distal ureter and the mechanisms mediating these effects

Ning Ding; Jiaxin Liu; Jianing Liu; Mengmeng Zhao; Lei Liu; Hanwen Liu; Jieke Yan; Wei Song; Jiliang Wen; Shulu Zu; Xiulin Zhang; Yang Xu

doi:10.1016/j.ejphar.2023.175715

The enhancing effect of 5-HT on phasic contractions of human isolated distal ureter and the mechanisms mediating these effects

Eur J Pharmacol. 2023 Jun 15:949:175715. doi: 10.1016/j.ejphar.2023.175715. Epub 2023 Apr 12.

Authors

Ning Ding¹, Jiaxin Liu², Jianing Liu³, Mengmeng Zhao¹, Lei Liu¹, Hanwen Liu¹, Jieke Yan³, Wei Song⁴, Jiliang Wen¹, Shulu Zu¹, Xiulin Zhang¹, Yang Xu⁵

Affiliations

¹ Department of Urology, The Second Hospital of Shandong University, Jinan, China.
² Department of Urology, The Second Hospital of Shandong University, Jinan, China; Department of Kidney Transplantation, The Second Hospital of Shandong University, Jinan, China.
³ Department of Kidney Transplantation, The Second Hospital of Shandong University, Jinan, China.
⁴ Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁵ Department of Urology, The Second Hospital of Shandong University, Jinan, China. Electronic address: xuyang2023@sdu.edu.cn.

PMID: 37059373
DOI: 10.1016/j.ejphar.2023.175715

Abstract

5-Hydroxytryptamine (5-HT) can enhance human ureteral contractions. However, the mediating receptors have not been clarified. This study sought to further characterize the mediating receptors using several selective antagonists and agonists. Human distal ureters were obtained from 96 patients undergoing cystectomy. The mRNA expression levels of 5-HT receptors were examined using RT-qPCR experiments. The phasic contractions of ureter strips, either spontaneous or evoked with neurokinin, were recorded in an organ bath. Among the 13 5-HT receptors, 5-HT_2A and 5-HT_2C receptors showed the highest mRNA expression levels. 5-HT (10^-7-10^-4 M) increased the frequency and baseline tension of phasic contractions in a concentration-dependent manner. However, a desensitization effect was observed. The 5-HT_2C receptor selective antagonist, SB242084 (10,30,100 nM), shifted the 5-HT concentration-response curves (frequency and baseline tension) rightward with a pA2 value of 8.05 and 7.75, respectively. 5-HT_2C receptor selective agonist, vabicaserin, increased contraction frequency with an Emax of 35% of 5-HT. 5-HT_2A receptor selective antagonist, volinanserin (1,10,100 nM), only reduced baseline tension with a pA2 of 8.18. The selective antagonists of 5-HT_1A, 1B, 1D, 2B, 3, 4, 5, 6, and 7 had no antagonism. Blockade of voltage-gated sodium channels, α1-adrenergic receptors, adrenergic neurotransmission, and neurokinin-2 receptors using tetrodotoxin, tamsulosin, guanethidine, and Men10376, respectively, and desensitization of sensory afferents using capsaicin (100 μM), significantly reduced 5-HT effects. We conclude that 5-HT enhanced ureteral phasic contractions mainly by activating 5-HT_2C and 5-HT_2A receptors. Sympathetic nerve and sensory afferents partly contributed to 5-HT effects. 5-HT_2C and 5-HT_2A receptors could be promising targets for ureteral stone expulsion.

Keywords: 5-HT agonists and antagonists; 5-HT(2C) receptors; 5-hydroxytryptamine; Human distal ureter; Phasic contractions.

MeSH terms

Humans
Muscle Contraction
RNA, Messenger
Receptor, Serotonin, 5-HT2C
Serotonin* / pharmacology
Serotonin* / physiology
Ureter*

Substances

Serotonin
Receptor, Serotonin, 5-HT2C
RNA, Messenger