The role of 5-HT2 receptor subtypes in the control of the urethra and the micturition reflex in anaesthetised female rats

Y.Mbaki, S. Westbrook1 & A.G. Ramage, Department of Pharmacology, University College London, Hampstead Campus, London, NW3 2PF, 1Discovery Biology, Pfizer Global Research and Development, Kent, CT13 9NJ.

5-HT receptors are implicated in the control of the bladder, however, little is known of their role in control of the urethra. Nevertheless, 5-HT2 receptor activation by mCPP was reported to increase cavernous nerve activity (Steers & De Groat, 1989). The present experiments were carried out to investigate the effect of the 5-HT2 receptor agonists, mCPP, Ro 60-0175, DOI (see Knight et al. 2004) and WAY 161503 (Cryan et al. 2000) on urethral pressure and sphincter (EUS) EMG activity and the micturition reflex.

Simultaneous recordings of EUS-EMG activity, urethral and bladder pressure, BP and HR were obtained from urethane-anaesthetised (1.2 g kg-1), spontaneously breathing female Sprague-Dawley rats (200-300g). Micturition reflexes were evoked by saline infusion (0.1 ml min -1) into the bladder. All test substances were given i.v. Changes in EUS-EMG activity, urethral and bladder pressure, BP and HR were compared with those in vehicle controls using two-way ANOVA and the least significant difference test. Changes in the micturition reflex were compared with vehicle controls using unpaired Student’s t-test. All values are expressed as the mean ± s.e.mean. P < 0.05 was considered to be significant.

WAY 161503, Ro 60-0175, mCPP, (300 μg kg-1, n=5) and DOI (100 μg kg-1, n=5) each caused a significant increase in baseline EUS-EMG activity (179± 9%, 150±13%, 166±17%, & 198±15%). Only WAY 161503, Ro 60-0175 and mCPP significantly increased urethral pressure (10±2%, 13±2% & 24±2%). The selective 5-HT2A receptor antagonist, (Knight et al. 2004) ketanserin (30 μg kg-1, n=5), blocked the effects of either WAY 161503 or DOI on EUS-EMG but not the ability of WAY 161503 to increase urethral pressure. The selective 5-HT2A receptor antagonist, MDL 100907 (30 μg kg -1, n=3), also antagonised the effect of DOI on EUS-EMG. mCPP blocked the micturition reflex, whereas WAY 161503 and Ro 60-0175 significantly increased bladder threshold pressure (25±11% & 90±33%) and volume threshold (55±13% & 71±15%). DOI significantly decreased the volume (-35±7%) but not the pressure threshold. Ketanserin potentiated the effects of WAY 161503 on volume but not pressure threshold, while it blocked the effect of DOI on volume threshold.

These data indicates that activation of 5-HT2A receptors evokes excitation of the external urethral sphincter, whereas it would seem that 5-HT2C receptor activation causes constriction of urethral smooth muscle and inhibition of the micturition reflex.

Cyran, JF & Lucki, I (2000) J Pharmacol Exp Ther; 295, 1120-1126.
Steers, WD & De Groat, WC, (1989) Am J Physiol; 257, R1441-R1449.
Knight , ARet al. , (2004) Naunyn Schmiedeb Arch Pharmacol; 370, 114-123.

YM is in receipt of BBSRC PhD collaborative award with Pfizer.